Biophysical study of resin acid effects on phospholipid membrane structure and properties.

Hydrophobic resin acids (RAs) are synthesized by conifer trees as part of their defense mechanisms. One of the functions of RAs in plant defense is suggested to be the perturbation of the cellular membrane. However, there is a vast diversity of chemical structures within this class of molecules, and there are no clear correlations to the molecular mechanisms behind the RA's toxicity. In this study we unravel the molecular interactions of the three closely related RAs dehydroabietic acid, neoabietic acid, and the synthetic analogue dichlorodehydroabietic acid with dipalmitoylphosphatidylcholine (DPPC) model membranes and the polar lipid extract of soybeans. The complementarity of the biophysical techniques used (NMR, DLS, NR, DSC, Cryo-TEM) allowed correlating changes at the vesicle level with changes at the molecular level and the co-localization of RAs within DPPC monolayer. Effects on DPPC membranes are correlated with the physical chemical properties of the RA and their toxicity.

Grafted biomembranes containing membrane proteins--the case of the leucine transporter.

Here, we bind the sodium dependent amino acid transporter on nitrilotriacetic acid/polyethylene glycol functionalized gold sensors in detergents and perform a detergent-lipid exchange with phosphatidylcholine. We characterize the LeuT structure in the adsorbed film by magnetic contrast neutron reflection using the predicted model from molecular dynamic simulations.

Synthesis and thermotropic phase behavior of four glycoglycerolipids.

Four glycoglycerolipids with different head groups have been synthesized and their physicochemical properties studied. The lengths of the head groups from a mono-saccharide to a trisaccharide, in addition to the anomeric stereochemistry for the smaller glycoglycerolipids, have been modified. The synthesis has been optimized to avoid glycerol epimerization and to allow up-scaling. The physicochemical properties of the glycoglycerolipids were studied and a strong de-mixing of the gel-phase, depending on the head-group, was observed.

Labeling of Disease-Modifying Therapies for Neurodegenerative Disorders.

Neurodegenerative disorders are characterized by progressive degeneration of nerve cells resulting in functional decline of cognition and/or movement. As the prevalence of many of these disorders increases with the aging global population, there is an urgent need for disease-modifying drugs that will halt or slow the progression of these devastating diseases. A summary of the scientific information needed to guide the safe and effective use of a drug is provided in the product label in which the indication section should clearly state the treatment concept, e.g., distinguish between symptomatic, preventive, and curative treatments. However, a review of the United States (US) and European Union (EU) product labels for disease-modifying multiple sclerosis (MS) drugs reveals that the indications are not aligned with the regulatory guidance on labeling. Indication claims such as "delay of accumulation of disability" and "slowing of disease progression" were previously accepted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, all recently approved MS drugs include no such specification of the treatment concept in the label indication sections despite similar clinical data packages supporting the approvals. Coincidently, the FDA and EMA therapeutic guidelines pertaining to development of drugs for treatment of neurodegenerative disorders have changed from providing recommendations for specific disease modification label claims to a more general focus on the clinical development approach. Our analysis of MS drug labels could imply that the FDA and EMA may be unlikely to accept disease modification-related indication claims for drugs to treat neurodegenerative disorders in general. We envision that a potential disease-modifying effect is more likely to be inferred from the label descriptions of the mechanism of action, clinical efficacy data and trial design, and target patient population. This poses a challenge for communication of the clinical benefit in a language that can be easily understood by patients and prescribers.

Characteristics of Single Pivotal Trials Supporting Regulatory Approvals of Novel Non-orphan, Non-oncology Drugs in the European Union and United States from 2012-2016.

For regulatory approval of a new medicine, the gold standard for demonstration of efficacy has traditionally been a minimum of two positive, adequate, and well-controlled clinical trials. Nevertheless, drugs to treat cancer and rare diseases are usually approved based on a single and often uncontrolled pivotal trial. In contrast, little is known about single pivotal trial approvals for non-orphan, non-oncology drugs. Between 2012 and 2016, 23 novel therapeutic drugs were approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for 27 non-orphan, non-oncology indications each based on a single pivotal trial. Although there was considerable variation in the nature and strength of the efficacy evidence supporting these drug approvals, the majority (85%) of the pivotal trials were randomized and controlled. For all superiority trials, the primary outcome was met with a statistical significance of P ≤ 0.005. Most approvals were supported by additional efficacy data from nonpivotal studies.

Key Factors Regulating the Mass Delivery of Macromolecules to Model Cell Membranes: Gravity and Electrostatics.

We show that both gravity and electrostatics are key factors regulating interactions between model cell membranes and self-assembled liquid crystalline aggregates of dendrimers and phospholipids. The system is a proxy for the trafficking of reservoirs of therapeutic drugs to cell membranes for slow diffusion and continuous delivery. Neutron reflectometry measurements were carried out on supported lipid bilayers of varying charge and on hydrophilic silica surfaces. Translocation of the macromolecule across the membrane and adsorption of the lamellar aggregates occur only when the membrane (1) is located above the bulk liquid and (2) has sufficient negative charge. The impact of such dramatic directionality effects due to bulk phase separation and gravity is emphasized for future biochemical investigations. Further, the potential to switch on the interaction mechanism through tuning the charge of the aggregates to activate endocytosis pathways on specific cell types is discussed in the context of targeted drug delivery applications.

The bidirectional tumor--mesenchymal stromal cell interaction promotes the progression of head and neck cancer.

INTRODUCTION: Mesenchymal stromal cells (MSC) are an integral cellular component of the tumor microenvironment. Nevertheless, very little is known about MSC originating from human malignant tissue and modulation of these cells by tumor-derived factors. The aim of this study was to isolate and characterize MSC from head and neck squamous cell carcinoma (HNSCC) and to investigate their interaction with tumor cells. METHODS: MSC were isolated from tumor tissues of HNSCC patients during routine oncological surgery. Immunophenotyping, immunofluorescence and in vitro differentiation were performed to determine whether the isolated cells met the consensus criteria for MSC. The cytokine profile of tumor-derived MSC was determined by enzyme-linked immunosorbent assay (ELISA). Activation of MSC by tumor-conditioned media was assessed by measuring cytokine release and expression of CD54. The impact of MSC on tumor growth in vivo was analyzed in a HNSCC xenograft model. RESULTS: Cells isolated from HNSCC tissue met the consensus criteria for MSC. Tumor-derived MSC constitutively produced high amounts of interleukin (IL)-6, IL-8 and stromal cell-derived factor (SDF)-1α. HNSCC-derived factors activated MSC and enhanced secretion of IL-8 and expression of CD54. Furthermore, MSC provided stromal support for human HNSCC cell lines in vivo and enhanced their growth in a murine xenograft model. CONCLUSIONS: This is the first study to isolate and characterize MSC from malignant tissues of patients with HNSCC. We observed cross-talk of stromal cells and tumor cells resulting in enhanced growth of HNSCC in vivo.