Raman Spectral Variation for Human Fingernails of Postmenopausal Women is Dependent on Fracture Risk and Osteoporosis Status

Patients diagnosed with osteoporosis have reported loss of fingernail resilience as the disease progresses. Keratin is the predominant protein in human nail tissue, and its structure has been postulated to be different in fingernails clipped from subjects who have sustained fragility fractures and those who have not, which may offer a window into the donor\u27s bone health. This study was designed to qualify these differences, which may lead to the development of a novel screening tool for fracture risk. Raman spectroscopy was used to measure the fingernails of 633 postmenopausal women who presented at six fracture clinics located across the UK and Ireland. The Raman signals from donor\u27s fingernails were compared between (1) fracture and nonfracture and (2) osteoporotic versus non-osteoporotic donors The data presented show differences in the protein changes observed for pervasive osteoporosis compared to a general increased risk of fragility fracture. For fracture risk, compositional changes falling into broad classes of amino acid residue (aliphatic, aromatic, acidic, amide and sulphurous) were observed, while a difference in disulphide bonding levels was reaffirmed. For pervasive osteoporosis, the disulphide mode suggested increasing disorder in disulphide bonding orientation. Fractures were associated with a transition from alpha helical secondary structure to random, while the pervasive osteoporosis cases were associated with a transition to beta sheet structure. General fracture risk is associated with a change in the structure and composition of the keratin protein. Osteoporosis is associated with different protein structural changes and an increase in free acid groups. Copyright © 2017 John Wiley & Sons, Ltd

Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells.

BACKGROUND: Successful delivery of small interfering RNA (siRNA) to the lungs remains hampered by poor intracellular delivery, vector-mediated cytotoxicity, and an inability to withstand nebulization. Recently, a novel cyclodextrin (CD), SC12CDClickpropylamine, consisting of distinct lipophilic and cationic subunits, has been shown to transfect a number of cell types. However, the suitability of this vector for pulmonary siRNA delivery has not been assessed to date. To address this, a series of high-content analysis (HCA) and postnebulization assays were devised to determine the potential for CD-siRNA delivery to the lungs. METHODS: SC12CDClickpropylamine-siRNA mass ratios (MRs) were examined for size and zeta potential. In-depth analysis of nanocomplex uptake and toxicity in Calu-3 bronchial epithelial cells was examined using IN Cell(®) HCA assays. Nebulized SC12CDClickpropylamine nanocomplexes were assessed for volumetric median diameter (VMD) and fine particle fraction (FPF) and compared with saline controls. Finally, postnebulization stability was determined by comparing luciferase knockdown elicited by SC12CDClickpropylamine nanocomplexes before and after nebulization. RESULTS: SC12CDClickpropylamine-siRNA complexation formed cationic nanocomplexes of ≤200 nm in size depending on the medium and led to significantly higher levels of siRNA associated with Calu-3 cells compared with RNAiFect-siRNA-treated cells at all MRs (p CONCLUSIONS: SC12CDClickpropylamine nanocomplexes can be effectively nebulized for pulmonary delivery of siRNA using Aeroneb technology to mediate knockdown in airway cells. To the best of our knowledge, this is the first study examining the suitability of SC12CDClickpropylamine-siRNA nanocomplexes for pulmonary delivery. Furthermore, this work provides an integrated nanomedicine-device combination for future in vitro and in vivo preclinical and clinical studies of inhaled siRNA therapeutics

Draft Genome Sequences of Six Different Staphylococcus epidermidis Clones, Isolated Individually from Preterm Neonates Presenting with Sepsis at Edinburgh\u27s Royal Infirmary

Herein, we report the draft genome sequences of six individual Staphylococcus epidermidis clones, cultivated from blood taken from different preterm neonatal sepsis patients at the Royal Infirmary, Edinburgh, Scotland, United Kingdom

Can non-viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics?

Cancer is one of the most wide-spread diseases of modern times, with an estimated increase in the number of patients diagnosed worldwide, from 11.3 million in 2007 to 15.5 million in 2030 (www.who.int). In many cases, due to the delay in diagnosis and high increase of relapse, survival rates are low. Current therapies, including surgery, radiation and chemotherapy, have made significant progress, but they have many limitations and are far from ideal. Although immunotherapy has recently offered great promise as a new approach in cancer treatment, it is still very much in its infancy and more information on this approach is required before it can be widely applied. For these reasons effective, safe and patient-acceptable cancer therapy is still largely an unmet clinical need. Recent knowledge of the genetic basis of the disease opens up the potential for cancer gene therapeutics based on siRNA. However, the future of such gene-based therapeutics is dependent on achieving successful delivery. Extensive research is ongoing regarding the design and assessment of non-viral delivery technologies for siRNA to treat a wide range of cancers. Preliminary results on the first human Phase I trial for solid tumours, using a targeted non-viral vector, illustrate the enormous therapeutic benefits once the issue of delivery is resolved. In this review the genes regulating cancer will be discussed and potential therapeutic targets will be identified. The physiological and biochemical changes caused by tumours, and the potential to exploit this knowledge to produce bio-responsive ‘smart’ delivery systems, will be evaluated. This review will also provide a critical and comprehensive overview of the different non-viral formulation strategies under investigation for siRNA delivery, with particular emphasis on those designed to exploit the physiological environment of the disease site. In addition, a section of the review will be dedicated to pre-clinical animal models used to evaluate the stability, safety and efficacy of the delivery systems

Multicenter evaluation of an intrapericardial left ventricular assist system

Objectives: The aim of this study was to conduct an initial clinical evaluation of the new HeartWare Ventricular Assist System (HeartWare, Inc., Framingham, Massachusetts) in a multicenter, prospective, nonrandomized single-arm clinical trial. Background: Heart failure is a worldwide epidemic. The effectiveness of heart transplantation and medical therapy is limited, resulting in the emergence of mechanical circulatory support as a primary treatment for end-stage heart disease. Left ventricular assist devices that use rotary pumps are small and durable, which might reduce morbidity and mortality during support. Methods: Fifty heart transplant candidates with New York Heart Association functional class IV symptoms were supported at 5 international centers by the HeartWare System for 180 days, until heart transplant, myocardial recovery and device explant, or death. Patients who continue to be supported have been followed for a minimum of 2 years. Results: Of the 50 patients, 20 (40%) received transplants, 4 (8%) had the pump explanted after myocardial recovery, and 17 (34%) continue support at 2 years. Nine (18%) patients died during support from sepsis (n = 3), multiple organ failure (n = 3), or hemorrhagic stroke (n = 3). The actual survival at 6, 12, and 24 months was 90%, 84%, and 79%, respectively. In the survivors, measures of quality of life showed a significant improvement over baseline values. Significant improvements were found for recognition memory at 3 months after implant (p = 0.006). The most frequent adverse events were infection and bleeding. Conclusions: Patients with end-stage heart failure can be safely and effectively supported by the HeartWare Ventricular Assist System with improved quality of life and neurocognitive function

Meeting breast cancer patients\u27 information needs during radiotherapy: What can we do to improve the information and support that is currently provided?

Previous research has reported that patients require specific information relating to radiotherapy; however, these studies fail to describe patients\u27 specific information needs over time. The aims of this study were to determine the specific information needs of breast cancer patients who are receiving radiotherapy and identify when patients prefer to receive specific information. Semi-structured interviews were conducted with 34 early breast cancer patients and 14 health professionals. Seventeen patients were interviewed after treatment completion, and 17 patients were interviewed on at least two occasions during their radiotherapy. Grounded theory and the constant comparative method were used to analyse the data. Three main categories emerged from the data: ‘repertoire of information’, ‘amount of information relating specifically to radiotherapy’ and‘tailoring information to match patients’ radiotherapy journeys\u27. Patients\u27 information needs were identified, and key messages and strategies to inform patients were described. This paper identifies breast cancer patient\u27s specific information needs during radiotherapy and shows that patients\u27 information needs are highest during their first appointment with their radiation oncologist and at the time of their planning appointment. The findings presented will enable health professionals to develop and refine their approaches to patient education in radiotherapy

Formulation and evaluation of anisamide-targeted amphiphilic cyclodextrin nanoparticles to promote therapeutic gene silencing in a 3D prostate cancer bone metastases model

In recent years, RNA interference (RNAi) has emerged as a potential therapeutic offering the opportunity to treat a wide range of diseases, including prostate cancer. Modified cyclodextrins have emerged as effective gene delivery vectors in a range of disease models. The main objective of the current study was to formulate anisamide-targeted cyclodextrin nanoparticles to interact with the sigma receptor (overexpressed on the surface of prostate cancer cells). The inclusion of octaarginine in the nanoparticle optimized uptake and endosomal release of siRNA in two different prostate cancer cell lines (PC3 and DU145 cells). Resulting nanoparticles were less than 200 nm in size with a cationic surface charge (∼+20 mV). In sigma receptor-positive cell lines, the uptake of anisamide-targeted nanoparticles was reduced in the presence of the sigma receptor competitive ligand, haloperidol. When cells were transfected in 2D, the levels of PLK1 mRNA knockdown elicited by targeted versus untargeted nanoparticles tended to be greater but the differences were not statistically different. In contrast, when cells were grown on 3D scaffolds, recapitulating bone metastasis, targeted formulations showed significantly higher levels of PLK1 mRNA knockdown (46% for PC3 and 37% for DU145,