Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'.

Identifying the core concepts of pharmacology education: A global initiative.

Background And Purpose: In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts.

Experimental Approach: We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master.

The role of Popeye domain-containing protein 1 (POPDC1) in the progression of the malignant phenotype.

The Popeye domain-containing protein 1 (POPDC1), a tight junction-associated transmembrane protein with a unique binding site for cAMP, has been shown to act as a tumour suppressor in cancer cells. Through interaction with many downstream effectors and signalling pathways, POPDC1 promotes cell adhesion and inhibits uncontrolled cell proliferation, epithelial-to-mesenchymal transition and metastasis. However, POPDC1 expression is down-regulated in many types of cancer, thereby reducing its tumour-suppressive actions.

Dysregulation of POPDC1 promotes breast cancer cell migration and proliferation.

Breast cancer subtypes such as triple-negative that lack the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2), remain poorly clinically managed due to a lack of therapeutic targets. This necessitates identification and validation of novel targets. Suppression of Popeye domain-containing protein 1 (POPDC1) is known to promote tumorigenesis and correlate to poor clinical outcomes in various cancers, and also promotes cardiac and skeletal muscle pathologies.

POPDC1 is suppressed in human breast cancer tissues and is negatively regulated by EGFR in breast cancer cell lines.

Breast cancer molecular heterogeneity has resulted in disparities in therapeutic response and targeting of molecular subtypes of breast cancer. This necessitates identification and validation of novel therapeutic targets for breast cancer treatment. Suppression of Popeye domain-containing (POPDC) proteins is hypothesized to promote malignant cell behaviour and poor clinical outcomes in various cancers.

POPDC proteins as potential novel therapeutic targets in cancer.

Popeye domain-containing (POPDC) proteins are a novel class of cAMP-binding molecules that affect cancer cell behaviour and correlate with poor clinical outcomes. They are encoded by the POPDC genes POPDC1, POPDC2, and POPDC3. The deletion of POPDC genes and the suppression of POPDC proteins correlate with enhanced cancer cell proliferation, migration, invasion, metastasis, drug resistance, and poor patient survival in various human cancers.

The cAMP-producing agonist beraprost inhibits human vascular smooth muscle cell migration via exchange protein directly activated by cAMP.

Aims: During restenosis, vascular smooth muscle cells (VSMCs) migrate from the vascular media to the developing neointima. Preventing VSMC migration is therefore a therapeutic target for restenosis. Drugs, such as prostacyclin analogues, that increase the intracellular concentration of cyclic adenosine monophosphate (cAMP) can inhibit VSMC migration, but the mechanisms via which this occurs are unknown.

A1-adenosine acute withdrawal response and cholecystokinin-8 induced contractures are regulated by Ca(2+)- and ATP-activated K(+) channels.

In isolated guinea-pig ileum (GPI), the A1-adenosine acute withdrawal response is under the control of several neuronal signalling systems, including the μ/κ-opioid and the cannabinoid CB1 systems. It is now well established that after the stimulation of the A1-adenosine system, the indirect activation of both μ/κ-opioid and CB1 systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated the involvement of the Ca(2+)/ATP-activated K(+) channels in the regulation of both acute A1-withdrawal and CCk-8-induced contractures in the GPI preparation.

The use of fluorescence resonance energy transfer (FRET) to measure axon growth and guidance-related intracellular signalling in live dorsal root ganglia neuronal growth cones.

The measurement of signalling by traditional methods in primary neuronal cultures is often limited by cell numbers within the culture and restricted division among these cells. Further limitations are seen with modern fluorescent imaging techniques on account of difficulties with transfection of these cell types. Here, we describe successful transfection of dorsal root ganglion (DRG) primary neuronal cultures with cDNA encoded fluorescence resonance energy transfer (FRET) probes for various signalling moieties, and subsequent measurement of FRET as an index of signalling within these cells.

Efficient cell transfection with melamine-based gemini surfactants.

Gemini surfactants consisting of two melamine scaffolds connected by a n-hexyl linker and functionalized with a 1-propylammonium polar head and a lipophilic chain having variable carbon length (from C8 to C16) were synthesized. These were then used successfully for the transfection of A549, U87 MG, and Bristol 8 cell lines with maxGFP expressing plasmid. The transfection protocol was optimized appropriately (confluence, reagent/pcDNA ratio, compaction time, and transfection time) for each cell line.

Mammalian growth cone turning assays identify distinct cell signalling mechanisms that underlie axon growth, guidance and regeneration.

The cell signalling mechanisms underlying mammalian central nervous system axon growth and guidance change during development, such that axons that establish appropriate connectivity in the embryo fail to regenerate after injury to the adult nervous system. The growth cone turning assay has been used in Xenopus neurons to elucidate mechanisms of axon guidance during development. Here, we describe how we have adapted this assay for rat dorsal root ganglion neurons to study the influence of extracellular secreted factors causing growth cone attraction and repulsion.

Chemical synthesis and biological activities of 3-alkyl pyridinium polymeric analogues of marine toxins.

Unlabelled: Two new large poly-1,3-dodecylpyridinium salts, APS12 and APS12-2 of 12.5- and 14.7-kDa size, respectively, were synthesised and tested for their pore-forming and transfection capabilities in HEK 293 and undifferentiated mouse ES cells using patch-clamp recording, Ca(2+) imaging and flow cytometry.

cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A.

cAMP is a key mediator of a number of molecules that induce growth cone chemotaxis, including netrin-1 and myelin-associated glycoprotein (MAG). Endogenous neuronal cAMP levels decline during development, and concomitantly axonal growth cones switch their response to cAMP-dependent guidance cues from attraction to repulsion. The mechanisms by which cAMP regulates these polarized growth cone responses are unknown.

Second-line combination chemotherapy with docetaxel and nedaplatin for Cisplatin-pretreated refractory metastatic/recurrent esophageal squamous cell carcinoma.

Background: There is an urgent need for an effective second-line chemotherapy regimen after failure of the standard cisplatin and 5-fluorouracil therapy.

Patients And Methods: This study investigated the efficacy and toxicity of the combination of docetaxel (30 mg/m2) during a 1-hour infusion, followed by nedaplatin (50 mg/m2) during a 2-hour infusion (both drugs were administered on day 1 as an outpatient regimen and repeated every 2 weeks) as second-line chemotherapy for patients with cisplatin-pretreated refractory metastatic/recurrent esophageal squamous cell carcinoma after surgery.

Results: Forty-six of the 48 patients (95.

First line chemotherapy with weekly docetaxel and cisplatin in elderly patients with advanced non-small cell lung cancer: a multicenter phase II study.

Introduction: We report outcomes for a phase II study of the combination of weekly docetaxel and cisplatin in elderly patients with advanced non-small cell lung cancer.

Methods: Patients with chemotherapy-naive, stage IIIB/IV, an Eastern Cooperative Oncology Group performance status of 0 or 1, ages 70 years or older, were eligible. Chemotherapy consisted of cisplatin (25 mg/m2) on days 1, 8, and 15 and docetaxel (20 mg/m2) on days 1, 8, and 15 every 4 weeks.

Multimarker circulating DNA assay for assessing blood of prostate cancer patients.

Background: Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients.

Elevated NF-kappaB responses and FLIP levels in leukemic but not normal lymphocytes: reduction by salicylate allows TNF-induced apoptosis.

As its name suggests, tumor necrosis factor (TNF) is known to induce cytotoxicity in a wide variety of tumor cells and cell lines. However, its use as a chemotherapeutic drug has been limited by its deleterious side effects of systemic shock and widespread inflammatory responses. Some nonsteroidal antiinflammatory drugs, such as sodium salicylate, have been shown to have a chemopreventive role in certain forms of cancer.

Successful treatment of metastatic androgen-independent prostate carcinoma in a transsexual patient.

The occurrence of prostate carcinoma in transsexual patients has rarely been reported. These cases present a unique challenge in that such patients are effectively receiving androgen deprivation therapy. By definition, their disease is androgen-independent prostate cancer, and the role of local therapy is undefined.

Expression of CYP2S1 in human hepatic stellate cells.

Activated stellate cells are myofibroblast-like cells associated with the generation of fibrotic scaring in chronically damaged liver. Gene chip analysis was performed on cultured fibrotic stellate cells. Of the 51 human CYP genes known, 13 CYP and 5 CYP reduction-related genes were detected with 4 CYPs (CYP1A1, CYP2E1, CY2S1 and CYP4F3) consistently present in stellate cells isolated from three individuals.

Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro.

Background & Aims: The activated pregnane X receptor is antifibrogenic in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of human pregnane X receptor activators on human hepatic stellate cell transdifferentiation to a profibrogenic phenotype in vitro.

Methods: Hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiate into profibrogenic myofibroblasts.

Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms.

The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16alpha-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo.

Switching leukemia cell phenotype between life and death.

Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis.

The influence of alkyl pyridinium sponge toxins on membrane properties, cytotoxicity, transfection and protein expression in mammalian cells.

The ability of two alkyl pyridinium sponge toxin preparations (poly-APS and halitoxin) to form transient pores/lesions in cell membranes and allow transfection of plasmid cDNA have been investigated using HEK 293 cells. Poly-APS and halitoxin preparations caused a collapse in membrane potential, reductions in input resistance and increased Ca2+ permeability. At least partial recovery was observed after poly-APS application but recovery was more rarely seen with halitoxin.