Search

A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12–16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36–1.41) and weeks 20–30 (odds ratio = 2.27, 95% confidence interval = 0.45–11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47–4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world.

Recent research in the field of nonviral gene delivery vectors has focused on preparing nanoparticles that are stabilized by the incorporation of a PEG coating and where one of the vector components is also cleavable. Here,we describe the synthesis, formulation, transfection properties, and biophysical studies of a PEG-stabilized ternary lipopolyplex vector in which, for the first time, both the lipid and peptide components are designed to be cleaved once the vector has been internalized. A series of cationic lipids, bearing short tri- or hexaethylene glycol groups, attached to the headgroup via an ester linkage, has been prepared. Trifunctional peptides have also been prepared, consisting of a Lys(16) sequence at the N-terminus (to bind and condense plasmid DNA); a spacer group (containing a sequence recognized and cleaved by endosomal enzymes) and an optional PEG4 amino acid; and an integrin-targeting cyclic peptide sequence (allowing the resulting nanoparticle to be internalized via receptor-mediated endocytosis). Differing combinations of these lipids and peptides have been formulated with DOPE and with plasmid DNA, and complex stability, transfection, and cleavage studies carried out. It was shown that optimal transfection activities in a range of cell types and complex stabilities were achieved with lipids bearing short cleavable triethylene glycol moieties, whereas the incorporation of PEG4 amino acids into the cleavable peptides had little effect. We have synthesized appropriate fluorescently labeled components and have studied the uptake of the vector, endosomal escape, peptide cleavage, and plasmid transport to the nucleus in breast cancer cells using confocal microscopy. We have also studied the morphology of these compact, stabilized vectors using cryo-EM.

Whilst developing a strategy for the solid-phase synthesis of lanthionine-containing peptides, we became aware of some problems with a previously published route for the synthesis of orthogonally-protected lanthionine. We report a structural reassignment of the key iodoalanine intermediate and resulting lanthionine derivatives.

We report a new approach to the on-resin synthesis of cyclic peptides containing unnatural thioether side-chain bridges. An orthogonally protected nor-lanthionine was incorporated in a linear precursor peptide via stepwise solid-phase synthesis. This was followed by double allyl deprotection, cyclisation using PyAOP and subsequent chain-extension to give an analogue of ring C of nisin.

The structure, biophysical properties and biological behavior of lipopolyplex ternary gene delivery vectors incorporating novel C14 glycerol based lipids of varying alkyl chain geometry (containing cis, trans or alkyne double bonds) have been studied in the presence and absence of a bifunctional targeting peptide designed to both condense DNA and confer integrin-specific targeting. In vitro transfection studies in breast cancer MDA-MB-231 cells revealed that ternary formulations of lipid:peptide:DNA (LPD) complexes prepared using the aforementioned lipids possessed highly synergistic transfection activity up to 2500-fold higher than their respective lipid:DNA (LD) or peptide:DNA (PD) counterparts. Furthermore, the small structural differences in the lipid alkyl chain geometries also resulted in pronounced differences in transfection within each type of formulation, whereby the trans lipids showed best activity when formulated as LD complexes, whereas the cis lipids were superior in LPD formulations. Confocal fluorescence internalization studies using labeled components of the formulations showed both the lipid and the DNA of LD complexes to be trapped in endocytic compartments, whereas in the case of LPD complexes, the DNA was clearly released from the endosomal compartments and, together with the peptide, internalized within the cell nucleus. Physicochemical characterization of the formulations carried out by light and neutron scattering, zeta potential measurement, and negative staining electron microscopy detected major structural differences between LD and LPD complexes. Gel electrophoresis assays additionally showed differences between the individual lipids tested in each type of formulation. In conclusion, the superior transfection of the trans lipids in the LD complexes was thought to be attributed to superior DNA binding caused by a more closely matched charge distribution of the more rigid, trans lipids with the DNA. In the case of the LPD complexes, the DNA was thought to be predominantly condensed by the cationic portion of the peptide forming a central core surrounded by a lipid bilayer from which the targeting sequence partially protrudes. The more fluid, cis lipids were thought to confer better activity in this formulation due to allowing more of the targeting peptide sequence to protrude.