The COPD assessment test and the modified Medical Research Council scale are not equivalent when related to the maximal exercise capacity in COPD patients

Introduction: The management and treatment of Chronic Obstructive Pulmonary Disease (COPD) are based on a cutoff point either of ≥ 10 on the COPD Assessment Test (CAT) or of ≥ 2 of the Medical Research Council (mMRC). Up to now, no study has assessed the equivalence between CAT and mMRC, as related to exercise tolerance in COPD. The aim of this study was to investigate as primary outcome the relationship between CAT and mMRC and maximal exercise capacity in COPD patients. We also evaluated as secondary outcome the agreement between CAT (≥ 10) and mMRC (≥ 2) to categorize patients according to their exercise tolerance. Material and methods: 118 consecutive COPD patients (39 females), aged between 47 and 85 years with a wide range of airflow obstruction and lung hyperinflation were studied. Maximal exercise capacity was assessed by cardiopulmonary exercise test. Results: CAT and mMRC scores were significantly related to VO2 peak (p<0.01). CAT (≥ 10) and mMRC (≥ 2) have a high likelihood to be associated to a value of VO2 peak less than 15.7 and 15.6 mL/kg/min, respectively. The interrater agreement between CAT (≥ 10) and mMRC (≥ 2) was found to be fair (κ = 0.20) in all patients but slight when they were subdivided in those with VO2 peak < 15 mL/kg/min and in those with VO2 peak ≥ 15 mL/kg/min (κ = 0.10 and κ = 0.20 respectively). Conclusion: This study shows that CAT and mMRC are useful tools to predict exercise tolerance in COPD, but they cannot be considered as supplementary measures

The Fate of Intranasally Instilled Silver Nanoarchitectures

The intranasal administration of drugs allows an effective and noninvasive therapeutic action on the respiratory tract. In an era of rapidly increasing antimicrobial resistance, new approaches to the treatment of communicable diseases, especially lung infections, are urgently needed. Metal nanoparticles are recognized as a potential last-line defense, but limited data on the biosafety and nano/biointeractions preclude their use. Here, we quantitatively and qualitatively assess the fate and the potential risks associated with the exposure to a silver nanomaterial model (i.e., silver ultrasmall-in-nano architectures, AgNAs) after a single dose instillation. Our results highlight that the biodistribution profile and the nano/biointeractions are critically influenced by both the design of the nanomaterial and the chemical nature of the metal. Overall, our data suggest that the instillation of rationally engineered nanomaterials might be exploited to develop future treatments for (non)communicable diseases of the respiratory tract

Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence

Background Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. In humans, its defective function is associated with cancer development and induces specific post-transcriptional alterations of gene expression. In this study, we seek to unbiasedly identify mRNAs regulated by dyskerin in human breast cancer-derived cells. Results We find that dyskerin depletion affects the expression and the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin in the cytoplasm in the form of shorter 3 ' snoRT fragments. We then characterize the whole cytoplasmic dyskerin RNA interactome and find both H/ACA box snoRTs and protein-coding transcripts which may be targeted by the snoRTs' guide properties. Since a fraction of these protein-coding transcripts is involved in the nuclear hormone receptor binding, we test to see if this specific activity is affected by dyskerin. Obtained results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer cells. These results are paralleled by consistent observations on the outcome of primary breast cancer patients stratified according to their tumor hormonal status. Accordingly, experiments in nude mice show that the reduction of dyskerin levels in estrogen-dependent cells favors xenograft development in the absence of estrogen supplementation. Conclusions Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions

Fumarate-loaded electrospun nanofibers with anti-inflammatory activity for fast recovery of mild skin burns

In the biomedical sector the availability of engineered scaffolds and dressings that control and reduce inflammatory states is highly desired, particularly for the management of burn wounds. In this work, we demonstrate for the first time, to the best of our knowledge, that electrospun fibrous dressings of poly(octyl cyanoacrylate) (POCA) combined with polypropylene fumarate (PPF) possess anti-inflammatory activity and promote the fast and effective healing of mild skin burns in an animal model. The fibers produced had an average diameter of (0.8  ±  0.1) µm and they were able to provide a conformal coverage of the injured tissue. The application of the fibrous mats on the burned tissue effectively reduced around 80% of the levels of pro-inflammatory cytokines in the first 48 h in comparison with un-treated animals, and enhanced skin epithelialization. From histological analysis, the skin thickness of the animals treated with POCA : PPF dressings appeared similar to that of one of the naïve animals: (13.7  ±  1.4) µm and (14.3  ±  2.5) µm for naïve and treated animals, respectively. The density of dermal cells was comparable as well: (1100  ±  112) cells mm−2 and (1358  ±  255) cells mm−2 for naïve and treated mice, respectively. The results demonstrate the suitability of the electrospun dressings in accelerating and effectively promoting the burn healing process

Galantamine-memantine hybrids for Alzheimer's disease: The influence of linker rigidity in biological activity and pharmacokinetic properties

Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations