Dynamics of aerosol size during inhalation : Hygroscopic growth of commercial nebulizer formulations

We thank the Elizabeth Blackwell Institute (EBI) for financial support through the EBI Early Career Research Fellowship awarded to AEH, and the EPSRC for financial support through a Leadership Fellowship awarded to JPR (grant reference EP/G007713/1). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are creditedThe size of aerosol particles prior to, and during, inhalation influences the site of deposition within the lung. As such, a detailed understanding of the hygroscopic growth of an aerosol during inhalation is necessary to accurately model the deposited dose. In the first part of this study, it is demonstrated that the aerosol produced by a nebulizer, depending on the airflows rates, may experience a (predictable) wide range of relative humidity prior to inhalation and undergo dramatic changes in both size and solute concentration. A series of sensitive single aerosol analysis techniques are then used to make measurements of the relative humidity dependent thermodynamic equilibrium properties of aerosol generated from four common nebulizer formulations. Measurements are also reported of the kinetics of mass transport during the evaporation or condensation of water from the aerosol. Combined, these measurements allow accurate prediction of the temporal response of the aerosol size prior to and during inhalation. Specifically, we compare aerosol composed of pure saline (150 mM sodium chloride solution in ultrapure water) with two commercially available nebulizer products containing relatively low compound doses: Breath, consisting of a simple salbutamol sulfate solution (5 mg/2.5 mL; 1.7 mM) in saline, and Flixotide Nebules, consisting of a more complex stabilized fluticasone propionate suspension (0.25 mg/mL; 0.5 mM in saline. A mimic of the commercial product Tobi (60 mg/mL tobramycin and 2.25 mg/mL NaC1, pH 5.5-6.5) is also studied, which was prepared in house. In all cases, the presence of the pharmaceutical was shown to have a profound effect on the magnitude, and in some cases the rate, of the mass flux of water to and from the aerosol as compared to saline. These findings provide physical chemical evidence supporting observations from human inhalation studies, and suggest that using the growth dynamics of a pure saline aerosol in a lung inhalation model to represent nebulizer formulations may not be representative of the actual behavior of the aerosolized drug solutions. (C) 2014 Published by Elsevier B.V.Peer reviewe

Quercetin Impact in Pancreatic Cancer: An Overview on Its Therapeutic Effects

Pancreatic cancer (PC) is a lethal malignancy cancer, and its mortality rates have been increasing worldwide. Diagnosis of this cancer is complicated, as it does not often present symptoms, and most patients present an irremediable tumor having a 5-year survival rate after diagnosis. Regarding treatment, many concerns have also been raised, as most tumors are found at advanced stages. At present, anticancer compounds-rich foods have been utilized to control PC. Among such bioactive molecules, flavonoid compounds have shown excellent anticancer abilities, such as quercetin, which has been used as an adjunctive or alternative drug to PC treatment by inhibitory or stimulatory biological mechanisms including autophagy, apoptosis, cell growth reduction or inhibition, EMT, oxidative stress, and enhancing sensitivity to chemotherapy agents. The recognition that this natural product has beneficial effects on cancer treatment has boosted the researchers’ interest towards more extensive studies to use herbal medicine for anticancer purposes. In addition, due to the expensive cost and high rate of side effects of anticancer drugs, attempts have been made to use quercetin but also other flavonoids for preventing and treating PC. Based on related studies, it has been found that the quercetin compound has significant effect on cancerous cell lines as well as animal models. Therefore, it can be used as a supplementary drug to treat a variety of cancers, particularly pancreatic cancer. This review is aimed at discussing the therapeutic effects of quercetin by targeting the molecular signaling pathway and identifying antigrowth, cell proliferation, antioxidative stress, EMT, induction of apoptotic, and autophagic features.The authors acknowledge the Molecular Medicine Research Center, Bio-Medicine Institute, Tabriz University of Medical Sciences, and the Clinical Research Development Unit of Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran. This work was supported and funded by Tabriz University of Medical Sciences, Tabriz, Iran (grant number: 68344)

An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus

Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3′ untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts

Estimation in a Competing Risks Proportional Hazards Model Under Length-biased Sampling With Censoring

International audienceWhat population does the sample represent? The answer to this question is of crucial importance when estimating a survivor function in duration studies. As is well-known, in a stationary population, survival data obtained from a cross-sectional sample taken from the population at time $t_0$ represents not the target density $f(t)$ but its length-biased version proportional to $tf(t)$, for $t>0$. The problem of estimating survivor function from such length-biased samples becomes more complex, and interesting, in presence of competing risks and censoring. This paper lays out a sampling scheme related to a mixed Poisson process and develops nonparametric estimators of the survivor function of the target population assuming that the two independent competing risks have proportional hazards. Two cases are considered: with and without independent consoring before length biased sampling. In each case, the weak convergence of the process generated by the proposed estimator is proved. A well-known study of the duration in power for political leaders is used to illustrate our results. Finally, a simulation study is carried out in order to assess the finite sample behaviour of our estimators

Highly multiplexed immune repertoire sequencing links multiple lymphocyte classes with severity of response to COVID-19

BACKGROUND: Disease progression of subjects with coronavirus disease 2019 (COVID-19) varies dramatically. Understanding the various types of immune response to SARS-CoV-2 is critical for better clinical management of coronavirus outbreaks and to potentially improve future therapies. Disease dynamics can be characterized by deciphering the adaptive immune response. METHODS: In this cross-sectional study we analyzed 117 peripheral blood immune repertoires from healthy controls and subjects with mild to severe COVID-19 disease to elucidate the interplay between B and T cells. We used an immune repertoire Primer Extension Target Enrichment method (immunoPETE) to sequence simultaneously human leukocyte antigen (HLA) restricted T cell receptor beta chain (TRB) and unrestricted T cell receptor delta chain (TRD) and immunoglobulin heavy chain (IgH) immune receptor repertoires. The distribution was analyzed of TRB, TRD and IgH clones between healthy and COVID-19 infected subjects. Using McFadden's Adjusted R2 variables were examined for a predictive model. The aim of this study is to analyze the influence of the adaptive immune repertoire on the severity of the disease (value on the World Health Organization Clinical Progression Scale) in COVID-19. FINDINGS: Combining clinical metadata with clonotypes of three immune receptor heavy chains (TRB, TRD, and IgH), we found significant associations between COVID-19 disease severity groups and immune receptor sequences of B and T cell compartments. Logistic regression showed an increase in shared IgH clonal types and decrease of TRD in subjects with severe COVID-19. The probability of finding shared clones of TRD clonal types was highest in healthy subjects (controls). Some specific TRB clones seems to be present in severe COVID-19 (Figure S7b). The most informative models (McFadden´s Adjusted R2=0.141) linked disease severity with immune repertoire measures across all three cell types, as well as receptor-specific cell counts, highlighting the importance of multiple lymphocyte classes in disease progression. INTERPRETATION: Adaptive immune receptor peripheral blood repertoire measures are associated with COVID-19 disease severity

Modeling and Efficient Control of Microturbine Generation System With Battery Energy Storage for Sensitive Loads

Microturbine generation system is one of the most promising and a fast growing distributed generation sources. It is used in various applications thanks to high efficiency, quick start and high reliability. Combination of the microturbine and storage system (e.g. battery bank) is desirable selection to satisfy the load requirements under all conditions and hence the battery bank can play an important role in restoring balance between source and demand. In this paper, modeling of the microturbine with battery energy storage system is presented to supply sensitive loads. Appropriate power exchange between battery and the microturbine is an essential issue so, a new control method is proposed for battery energy storage based on instantaneous value of DC-link voltage. In this new strategy, DC-link voltage as well as battery parameters (current and voltage) are used in order to produce desirable DC-DC switching. A control scheme based on voltage, current and frequency measurement is presented for the corresponding inverter. Simulations are carried out in MATLAB/Simulink software and the results show that storage along with proper control improves system reliability to supply sensitive load. The proposed configuration can be used as a remote power, emergency power and also in micro-grid

Phytochemical analysis and biological activity evaluation of essential oil of Scrophularia atropatana

Background and objectives: Scrophularia atropatana (S. atropatana) is endemic to western and central regions of Iran. It belongs to the genus of Scrophularia (family: Scrophulariaceae). These species have been found to possess antibacterial, antitumor and anti-inflammatory properties. Most of these effects were proven to be attributed to the non-volatile components, which were known as secondary metabolites. Iridoids, phenylpropanoids, phenolic acids and flavonoids have been identified as their main secondary metabolites. This investigation was performed to analyze the composition of the essential oil (EO) of S. atropatana and evaluation of its anti-oxidant and total toxicity properties. Methods: About 150 g powder of the air dried parts of S. atropatana was submitted to hydro-distillation and also was successively extracted (with n-hexane, dichloromethane (DCM) and methanol (MeOH)), by using Clevenger and Soxhlet apparatus, respectively. In addition, Essential Oil (EO) was analyzed by GC-MS and GC-FID. Furthermore, the anti-oxidant activity of the extracts, fractions and EO as well as general toxicity were investigated by DPPH and brine shrimp larva assay, respectively. Results: Totally, sixty eight volatile compounds were identified, which constituted 91.78% of the total oil composition. Among the compounds, major constituents were identified as non-terpenoides (59.59%). Moreover, among the extracts and EO, methanol extract demonstrated high free radical scavenging and general toxic activities with RC50 equal 0.143±0.13 mg/mL and LD50 0.271 mcg/mL respectively. Conclusion: Overall, the main constituents of S. atropatana were hydrocarbons. In comparison to other genesis of Scrophularia, antioxidant activity of the essential oil of S. atropatana was less noticeable