Preferred Educational Programming Among Graduate Students and Post-doctoral Fellows at Pharmacy Schools: a Pilot Survey.

Objective: To inform program development, the AACP Graduate Education Special Interest Group Colleagues in Training Committee (CITC) investigated professional development needs of graduate students and post-doctoral fellows at schools/colleges of pharmacy.

Methods: A cross-sectional pilot survey examined preferred programming topics, mentoring needs, and career goals. A survey invitation was posted on AACP Connect and emailed to Graduate Program Officers and Assistant/Associate Deans for Research at US pharmacy schools/colleges for distribution to trainees.

Inorganic nanoparticles incorporated with transdermal drug delivery systems.

Introduction: Transdermal drug delivery (TDD) is becoming more recognized as a noninvasive method particularly suitable for vulnerable populations. TDD offers an alternative to oral drug delivery, bypassing issues related to poor absorption and metabolism. However, the application of TDD is limited to a few drugs due to the skin's barrier.

Preclinical evaluation of ELP-004 in mice.

This study provides a detailed understanding of the preclinical pharmacokinetics and metabolism of ELP-004, an osteoclast inhibitor in development for the treatment of bone erosion. Current treatments for arthritis, including biological disease-modifying antirheumatic drugs, are not well-tolerated in a substantial subset of arthritis patients and are expensive; therefore, new treatments are needed. Pharmacokinetic parameters of ELP-004 were tested with intravenous, oral, and subcutaneous administration and found to be rapidly absorbed and distributed.

Multi-Year Study of the Chemical and Sensory Effects of Microwave-Assisted Extraction of Musts and Stems in Cabernet Sauvignon, Merlot and Syrah Wines from the Central Coast of California.

Microwave technology (MW) was applied to musts and stems over three consecutive vintages in Cabernet Sauvignon, Merlot and Syrah wines from California (USA). Stems were added to musts at a rate of 50 and 100% (50% Stems and 100% Stems), either as untreated or after MW (50% MW Stems and 100% MW Stems). Stem additions lowered ethanol (up to 1.

Implementation Science to Advance Practice and Curricular Transformation: Report of the 2019-2020 AACP Research and Graduate Affairs Committee.

The 2019-2020 AACP Research and Graduate Affairs Committee (RGAC) was charged with articulating the case for and evaluating the state of implementation science in academic pharmacy, given the potential for implementation science to act as a driver of practice and curricular transformation. Based on the current state of pharmacy research in this area, the RGAC was further charged with outlining a plan to raise the profile of implementation science with pharmacy leadership and defining strategies for AACP to facilitate schools in applying its methods to their practice and education missions. For this work, the RGAC considered implementation science to be the scientific study of methods and strategies to promote adoption of evidence-based practices and interventions into real world settings and routine practice, to improve the quality and effectiveness of services.

Appropriateness of Term Limits for Administrative Appointments in Pharmacy Programs.

The appropriateness of term limits for administrative appointments is a subject of much discussion, not just within pharmacy programs, but in organizations of all types. The prospect of term limits for involves a wide variety of important organizational issues, including succession planning, institutional memory, strategic decision-making, and concepts regarding leadership styles overall. This paper examines both sides of the debate regarding the appropriateness of term limits for administrative appointments.

C8-Guanine modifications: effect on Z-DNA formation and its role in cancer.

Base modifications are known to affect the structure and function of DNA. C8-guanine adducts from various carcinogenic compounds have been shown to be potent Z-DNA inducers. Hence, it has been hypothesized that Z-DNA plays a role in cancer and other genetic diseases.

Immobilized Cytochrome P450 for Monitoring of P450-P450 Interactions and Metabolism.

Cytochrome P450 (P450) protein-protein interactions have been shown to alter their catalytic activity. Furthermore, these interactions are isoform specific and can elicit activation, inhibition, or no effect on enzymatic activity. Studies show that these effects are also dependent on the protein partner cytochrome P450 reductase (CPR) and the order of protein addition to purified reconstituted enzyme systems.

Selection of Single-Stranded DNA Molecular Recognition Elements against Exotoxin A Using a Novel Decoy-SELEX Method and Sensitive Detection of Exotoxin A in Human Serum.

Exotoxin A is one of the virulence factors of Pseudomonas aeruginosa, a bacterium that can cause infections resulting in adverse health outcomes and increased burden to health care systems. Current methods of diagnosing P. aeruginosa infections are time consuming and can require significant preparation of patient samples.

Nanoscale electron transport measurements of immobilized cytochrome P450 proteins.

Gold nanopillars, functionalized with an organic self-assembled monolayer, can be used to measure the electrical conductance properties of immobilized proteins without aggregation. Measurements of the conductance of nanopillars with cytochrome P450 2C9 (CYP2C9) proteins using conducting probe atomic force microscopy demonstrate that a correlation exists between the energy barrier height between hopping sites and CYP2C9 metabolic activity. Measurements performed as a function of tip force indicate that, when subjected to a large force, the protein is more stable in the presence of a substrate.

Single C8-Arylguanine modifications render oligonucleotides in the Z-DNA conformation under physiological conditions.

Z-DNA is the only DNA conformation that has a left-handed helical twist. Although Z-DNA has been implicated in both carcinogenesis and mutagenesis, its specific biological role remains uncertain. We have demonstrated that the formation of C8-arylguanine DNA adducts, derived from arylhydrazines, shifts the B/Z-DNA equilibrium toward the Z-DNA conformation in d(CG)5 sequences.

The use of immobilized cytochrome P4502C9 in PMMA-based plug flow bioreactors for the production of drug metabolites.

Cytochrome P450 enzymes play a key role in the metabolism of pharmaceutical agents. To determine metabolite toxicity, it is necessary to obtain P450 metabolites from various pharmaceutical agents. Here, we describe a bioreactor that is made by immobilizing cytochrome P450 2C9 (CYP2C9) to a poly(methyl methacrylate) surface and, as an alternative to traditional chemical synthesis, can be used to biosynthesize P450 metabolites in a plug flow bioreactor.

Measurement of electron transfer through cytochrome P450 protein on nanopillars and the effect of bound substrates.

Electron transfer in cytochrome P450 enzymes is a fundamental process for activity. It is difficult to measure electron transfer in these enzymes because under the conditions typically used they exist in a variety of states. Using nanotechnology-based techniques, gold conducting nanopillars were constructed in an indexed array.

A conformational NMR analysis of methymycin aglycones: complete and unambiguous assignments of stereochemically diverse glycosylated methymycin analogs by 1D and 2D NMR techniques and molecular modeling.

The (1)H and (13)C NMR spectra of 10-deoxymethynolide (1), 8.9-dihydro-10-deoxymethynolide (2) and its glycosylated derivatives (3-9) were analyzed using gradient-selected NMR techniques, including 1D TOCSY, gCOSY, 1D NOESY (DPFGSENOE), NOESY, gHMBC, gHSQC and gHSQC-TOCSY. The NMR spectral parameters (chemical shifts and coupling constants) of 1-9 were determined by iterative analysis.

Src binds cortactin through an SH2 domain cystine-mediated linkage.

Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins.

An investigation into the feasibility of myoglobin-based single-electron transistors.

Myoglobin single-electron transistors were investigated using nanometer-gap platinum electrodes fabricated by electromigration at cryogenic temperatures. Apomyoglobin (myoglobin without the heme group) was used as a reference. The results suggest single-electron transport is mediated by resonant tunneling with the electronic and vibrational levels of the heme group in a single protein.

Selective filling of nanowells in nanowell arrays fabricated using polystyrene nanosphere lithography with cytochrome P450 enzymes.

This work describes an original and simple technique for protein immobilization into nanowells, fabricated using nanopatterned array fabrication methods, while ensuring the protein retains normal biological activity. Nanosphere lithography was used to fabricate a nanowell array with nanowells 100 nm in diameter with a periodicity of 500 nm. The base of the nanowells was gold and the surrounding material was silicon dioxide.

Glutathione conjugation of busulfan produces a hydroxyl radical-trapping dehydroalanine metabolite.

The Phase 2 drug metabolism of busulfan yields a glutathione conjugate that undergoes a β-elimination reaction. The elimination product is an electrophilic metabolite that is a dehydroalanine-containing tripeptide, γ-glutamyldehydroalanylglycine (EdAG). In the process, glutathione lacks thiol-related redox properties and gains a radical scavenging dehydroalanine group.

The synthesis of C8-aryl purines, nucleosides and phosphoramidites.

C8-Aryl purines, their nucleosides, and phosphoramidites has been synthetic targets for more than 60 years. Interest in these compounds stems from their utility as fluorescent markers, they have therapeutic uses, are biomarkers, biomolecular probes, supramolecular building blocks, and for conformational studies. Until recently, the selective arylation of the C8-position of purines has been a challenging task.

The conformational effect of para-substituted C8-arylguanine adducts on the B/Z-DNA equilibrium.

The B form of DNA exists in equilibrium with the Z form and is mainly affected by sequence, electrostatic interactions, and steric effects. C8-purine substitution shifts the equilibrium toward the Z form though how this interaction overcomes the unfavorable electrostatic interactions and decrease in stacking in the Z form has not been determined. Here, a series of C8-arylguanine derivatives, bearing a para-substituent were prepared and the B/Z equilibrium determined.

A Polymorphic Variant of AFAP-110 Enhances cSrc Activity.

Enhanced expression and activity of cSrc are associated with ovarian cancer progression. Generally, cSrc does not contain activating mutations; rather, its activity is increased in response to signals that affect a conformational change that releases its autoinhibition. In this report, we analyzed ovarian cancer tissues for the expression of a cSrc-activating protein, AFAP-110.

A general synthesis of C8-arylpurine phosphoramidites.

A general scheme for the synthesis of C8-arylpurine phosphoramidites has been developed. C8-Arylation of C8-bromo-2'-deoxyguanosine is the key step and has been achieved through the use of a Suzuki coupling. Since the coupling reaction is conducted under aqueous conditions, it is unnecessary to protect and then deprotect the hydroxyl groups, thus saving several steps and improving overall yields.

Electrocatalytic drug metabolism by CYP2C9 bonded to a self-assembled monolayer-modified electrode.

Cytochrome P450 (P450) enzymes typically require the presence of at least cytochrome P450 reductase (CPR) and NADPH to carry out the metabolism of xenobiotics. To address whether the need for redox transfer proteins and the NADPH cofactor protein could be obviated, CYP2C9 was bonded to a gold electrode through an 11-mercaptoundecanoic acid and octanethiol self-assembled monolayer (SAM) through which a current could be applied. Cyclic voltammetry demonstrated direct electrochemistry of the CYP2C9 enzyme bonded to the electrode and fast electron transfer between the heme iron and the gold electrode.

Substrate proton to heme distances in CYP2C9 allelic variants and alterations by the heterotropic activator, dapsone.

CYP2C9 polymorphisms result in reduced enzyme catalytic activity and greater activation by effector molecules as compared to wild-type protein, with the mechanism(s) for these changes in activity not fully elucidated. Through T(1) NMR and spectral binding analyses, mechanism(s) for these differences in behavior of the variant proteins (CYP2C9.2, CYP2C9.

Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9.

Several laboratories have demonstrated that activation of drug metabolism by P450s may occur via a mechanism that resembles allosterism from an enzyme kinetic standpoint. Because the effector drug binding site may be located in the same P450 binding pocket where the drug substrate is located, the ability to find and characterize novel effectors (aka heteroactivators) will prove to be important in probing the mechanism of activation. We have used analogues of the prototypical CYP2C9 heteroactivator dapsone to validate a simple docking method that can be used to predict heteroactivators based on ligand binding location in a P450 crystal structure.