An Evaluation of Antibiotic Resistance: Structure-Activity Relationship Studies of Tetracyclic Indolines as A Novel Class of Resistance-Modifying Agents for MRSA & Analysis of Recent FDA Regulations on Antibiotic Use in Livestock

While the rate at which resistance develops against antimicrobials rises, research and development for new antimicrobials declines. By placing selective pressure on bacteria we are inadvertently forcing bacteria into expressing and propagating genes conferring high levels of resistance. Continued misuse and overuse of antibiotics, in light of the evident problem developing, must be resolved. To find a resolve, a multidisciplinary and multifaceted approach must be taken which involves 1) research and development of novel antimicrobial agents and 2) governmental regulation. Strides in new antimicrobial drug development largely revolve around making old antibiotics usable again. Resistance-Modifying Agents (RMAs) act to re-sensitize resistant bacteria to antibiotics through a variety of mechanisms, although currently most target bacterial resistance mechanisms themselves, such as &beta; - lactamases. Foreseeably, while these compounds have shown efficacy and certainly are of value in the present crisis, it is a short-term solution in light of the evidently rapid and dynamic capability of bacteria to respond evolutionarily. Nonetheless, a new class of RMAs, currently being researched and developed at Wang lab, hope to extend RMA lifespan through a model of synthetic compound development that targets gene expression. Both clinically and community-acquired resistance contribute to the demolishment of a critical building block (antibiotics) of modern medicine. Arguably the most nonsensical piece of the puzzle is subtherapeutic antibiotic use in livestock, which accounts for 80% of all antibiotic use in the United States12. FDA regulations are seemingly the only feasible way to fix the problem, and yet their efforts in recent regulatory measures not only contain major loopholes, but seem altogether to be largely barren of any significant resolutions.</p

Treatment of metastatic head and neck cancer with mesenchymal stem cells combined with prodrug gene therapy

This is a clinical observation of a patient treated for metastatic head and neck cancer with mesenchymal stem cells mediated prodrug gene therapy. The cells were applied intravenously. We did not observe any therapeutic effect. However, a temporal bicytopenia was observed. Key Words: metastatic head and neck cancer, therapeutic stem cells, blood counts

Lipoxin A and Serum Amyloid a Differentially Modulate Phospholipase D in Human Fibroblast-Like Synoviocytes

Lipoxin A 4 (LXA 4 ) and scrum amyloid A (SAA) are endogenous negative and positive modulators of inflammation, respectively. Both molecules bind the shared lipoxin A 4 receptor (ALX) and elicit opposing effects on the production of inflammatory cytokines and matrix metalloproteinases. The aim of these studies is to examine the divergence of the intracellular signaling pathways triggered by lipid LXA 4 (1 nM) and protein SAA (200 nM) ligands of ALX. Phospholipase D (PLD) is a phosphohydrolase enzyme that catalyzes the generation of phosphatidic acid (PA) from membrane phospholipids. Our results showed that in fibroblast-like synoviocytes, activation of PLD occurred only in response to LXA 4 , and not SAA. PA (30 μM) mimicked LXA 4 and demonstrated inhibition of IL-8 production induced by SAA or interleukin-1β. In sharp contrast to LXA 4 , SAA confirmed the stimulation of IL-8 release as determined previously. Taken together, these findings suggest that two physiologic ligands sharing the common ALX receptor, LXA 4 and SAA, differentially regulate the level of PLD activation and differentially modulate IL-8. These results may have important implications for understanding the regulation of inflammatory responses under physiologic and pathological conditions

High Avidity Anti-β2-Glycoprotein i Antibodies Activate Human Coronary Artery Endothelial Cells and Trigger Peripheral Blood Mononuclear Cell Migration

Anti-β2-glycoprotein I antibodies (aβ2GPI) represent a potential pathogenic candidate for coronary artery diseases. High avidity aβ2GPI (HAv aβ2GPI) are known to be associated with thrombotic and obstetric manifestations in patients with antiphospholipid syndrome, who are also susceptible to the development of premature atherosclerosis. However, there is little information about how human coronary artery endothelial cells (HCAEC) are affected by HAv aβ2GPI. The purpose of our study was to evaluate the pathophysiological effects of HAv aβ2GPI on HCAEC and determine their influence on cytokine expression and migration of peripheral blood mononuclear cells. Following the two hit hypothesis, we co-stimulated HAv aβ2GPI-treated HCAEC in the presence and absence of the acute phase protein serum amyloid A (SAA). HAv aβ2GPI induced in vitro HCAEC dysfunction, through the ERK1/2 signaling pathway, promoted the expression of chemokines (MCP-1, GROα and IL-8) and IL-6, which led to the attraction and migration of peripheral blood mononuclear cells. These effects were potentiated and intensified in conditions with SAA, indicating that HAv aβ2GPI, in the presence of physiological concentrations of acute-phase proteins represent pathogenic autoantibodies, which could lead to the development of premature atherosclerosis and/or thrombosis development