Parametric hierarchical matrix approach for the wideband optical response of large-scale molecular aggregates

Fast and efficient calculations of optical responses using electromagnetic models require computational acceleration and compression techniques. A hierarchical matrix approach is adopted for this purpose. In order to model large-scale molecular structures, these methods should be applied over wide frequency spectra. Here, we introduce a novel parametric hierarchical matrix method that allows one for a rapid construction of a wideband system representation and enables an efficient wideband solution. We apply the developed method to the modeling of the optical response of bacteriochlorophyll tubular aggregates as found in green photosynthetic bacteria. We show that the parametric method can provide one with the frequency and time-domain solutions for structures of the size of 100 000 molecules, which is comparable to the size of the whole antenna complex in a bacterium. The absorption spectrum is calculated and the significance of electrodynamic retardation effects for relatively large structures, i.e., with respect to the wavelength of light, is briefly studied. © 2013 AIP Publishing LLC

Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers

Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5 h, 21 h, and 72 h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21 h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72 h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21 h release dendrimer conjugate did not produce a high initial Cmax of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4 mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects

Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy

Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc

Deformability analysis and improvement in stretchable electronics systems through finite element analysis

Stretchable electronic systems employ a combination of extremely deformable substrates with electrically conductive inks printed on their surface, on which components are connected. The absence of solid metal as conductive material greatly enhances the deformability of these systems. However, although being able to sustain high deformation, the presence of rigid components heavily affects the achievable deformation levels due to strain concentrations near the interconnection area. In order to improve stretchability under these conditions, a combination of research on materials for conductive inks and optimization of the employed layout is needed. Especially for the latter, the use of Finite Element (FE) modeling is very useful, since it allows to locate critical regions for deformation behavior and to perform design optimization and instability analyses. In this work, the authors show the application of this strategy to improve mechano-electrical performance of the system under uniaxial tension by modelling and then modifying the overall stiffness of specific sample regions. Depending on the specific need, different strategies can be adopted to intervene on stiffness changes, such as material addition to specific regions. This work shows that, in particular, a simple technique such as laser cutting can be used to tailor the local material parameters at a deeper level, thus allowing decrease in stiffness gradients and a general enhancement of electrical performances under high levels of uniaxial deformation of the sample, as also predicted in the FE analyses.acceptedVersionPeer reviewe

Preparation and in vivo evaluation of nanoliposomes containing melphalan after intravitreal injection in albino rabbits

The aim of present study was to evaluate the stability and toxicity of different doses of liposomal melphalan in rabbit eyes and to investigate the pathological and electrophysiological changes after administration of different doses of free form of melphalan. Liposomes containing melphalan were prepared by solvent evaporation method and mean size of these liposomes and encapsulation efficacy of nanoliposomes were determined. In albino rabbits, intravitreal injections of 10, 20, and 40 µg doses of liposomal melphalan and Alkeran® as the commercial product was performed. The rabbits were euthanized at days 2, 7, 14, and 28, and the eyes were enucleated. Vitreous and aqueous samples and electrophysiological recordings were obtained before euthanization. Histological examination was performed after enucleation. Particle size of prepared liposomes was 143.6 ± 3.2 nm. Liposomes have protected melphalan completely from any undesirable release or hydrolysis for 48 h. In a histopathological study, signs of retinal toxicity were found in all doses in the liposomal group at least at one time point during the study. In melphalan injected eyes, histopathological toxicity was found in the 40 µg dose. Extensive variability was found in electrophysiological recordings, and significant waveform changes were found in all injected eyes at least on one occasion during the study. Intraocular administration of liposomal melphalan cannot prolong the drug clearance time of this drug in the vitreous humor. In the 40 µg injected eyes, significant retinal atrophic changes were detected in all eyes throughout the study, and electrophysiological results were consistent with histopathological findings. © 2016, The Korean Society of Pharmaceutical Sciences and Technology