1H NMR determination of the self-association of an acridine homodimer and its complexation with ethidium bromide in aqueous solution

1H NMR spectroscopy (500MHz) has been used to investigate the self-association in aqueous buffered solution of a bis-intercalator, Acridine Homodimer (AcrH), and its hetero-association with the aromatic dye, Ethidium Bromide (EB). The equilibrium constants and thermodynamical parameters (enthalpy and entropy) of self-association have been determined from the observed concentration and temperature dependences of chemical shifts of AcrH protons and the results are consistent with a model consisting of at least four distinct forms of AcrH molecules in solution: unfolded (U), folded (F), a dimer formed from two folded molecules (F2) and a trimer formed from three folded molecules (F3). It has also been shown that Ethidium Bromide complexes strongly to the dimer form (F2) of the bis-acridine molecule, AcrH. Comparison of the calculated association parameters of AcrH with the previously studied Ethidium Homodimer (EBH) revealed a correlation between the effectiveness of complexation and the length of chain connecting the chromophores of a bis-intercalator

A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

BACKGROUND: There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). METHODS: This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. RESULTS: Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. CONCLUSION: Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effector

tert-Butyl 6-bromo-1,4-dimethyl-9H-carbazole-9-carboxyl­ate

The title compound, C19H20BrNO2, consists of a carbazole skeleton with methyl groups at positions 1 and 4, a protecting group located at the N atom and a Br atom at position 6. The pyrrole ring is oriented at dihedral angles of 1.27 (7) and 4.86 (7)° with respect to the adjacent benzene rings. The dihedral angle between the benzene rings is 5.11 (7). The crystal structure is determined mainly by intra­molecular C—H⋯O and inter­molecular π–π inter­actions. π-stacking between adjacent molecules forms columns with a parallel arrangement of the carbazole ring systems. The presence of the tert-but­oxy­carbonyl group on the carbazole N atom and the intra­molecular hydrogen bond induce a particular conformation of the exocyclic N—C bond within the mol­ecule

X-ray crystallographic study of DNA duplex cross-linking: simultaneous binding to two d(CGTACG)(2) molecules by a bis(9-aminoacridine-4-carboxamide) derivative

Acridine-4-carboxamides form a class of known DNA mono-intercalating agents that exhibit cytotoxic activity against tumour cell lines due to their ability to inhibit topoisomerases. Previous studies of bis-acridine derivatives have yielded equivocal results regarding the minimum length of linker necessary between the two acridine chromophores to allow bis-intercalation of duplex DNA. We report here the 1.7 angstrom resolution X-ray crystal structure of a six-carbon-linked bis(acridine-4-carboxamide) ligand bound to d(CGTACG)(2) molecules by non-covalent duplex cross-linking. The asymmetric unit consists of one DNA duplex containing an intercalated acridine-4-carboxamide chromophore at each of the two CG steps. The other half of each ligand is bound to another DNA molecule in a symmetry-related manner, with the alkyl linker threading through the minor grooves. The two crystallographically independent ligand molecules adopt distinct side chain interactions, forming hydrogen bonds to either O6 or N7 on the major groove face of guanine, in contrast to the semi-disordered state of mono-intercalators bound to the same DNA molecule. The complex described here provides the first structural evidence for the non-covalent cross-linking of DNA by a small molecule ligand and suggests a possible explanation for the inconsistent behaviour of six-carbon linked bis-acridines in previous assays of DNA bis-intercalation

Nutritional situation for larval Atlantic herring (Clupea harengus L.) in two nursery areas in thewestern Baltic Sea

The Greifswalder Bodden (GWB) is considered to be the most important spawning and nursery area for the western Baltic spring-spawning herring. However, the biotic and abiotic reasons for this are still unclear. Consequently, we investigated larval growth conditions in the GWB and in the Kiel Canal (KC), another nursery and spawning area of Baltic herring. We investigated prey quantity and quality [copepod abundance and essential fatty acid (EFA) concentration] as well as biochemically derived growth rates and fatty acid content of larval herring in spring 2011. A significant correlation between larval growth and larval EFA concentration could be observed in the GWB. The highest growth rates and EFA concentrations in the larval herring coincided with high food quality. Compensating effects of food quality on food quantity and vice versa could be observed in both the GWB and the KC. While larval growth rates in the KC were high early in the season, highest growth rates in the GWB were achieved late in the season. In conclusion, neither area was superior to the other, indicating similar growth conditions for larval herring within the region

Food Quality Affects Secondary Consumers Even at Low Quantities: An Experimental Test with Larval European Lobster

The issues of food quality and food quantity are crucial for trophic interactions. Although most research has focussed on the primary producer – herbivore link, recent studies have shown that quality effects at the bottom of the food web propagate to higher trophic levels. Negative effects of poor food quality have almost exclusively been demonstrated at higher food quantities. Whether these negative effects have the same impact at low food availability in situations where the majority if not all of the resources are channelled into routine metabolism, is under debate. In this study a tri-trophic food chain was designed, consisting of the algae Rhodomonas salina, the copepod Acartia tonsa and freshly hatched larvae of the European lobster Homarus gammarus. The lobster larvae were presented with food of two different qualities (C∶P ratios) and four different quantities to investigate the combined effects of food quality and quantity. Our results show that the quality of food has an impact on the condition of lobster larvae even at very low food quantities. Food with a lower C∶P content resulted in higher condition of the lobster larvae regardless of the quantity of food. These interacting effects of food quality and food quantity can have far reaching consequences for ecosystem productivity