Hematotoxicity of magnetite nanoparticles coated with polyethylene glycol: in vitro and in vivo studies

Accepted Manuscript.-- et al.Hematotoxicity of magnetite nanoparticles coated with dimercaptosuccinic acid (DMSA) and polyethylene glycol (PEG) has been evaluated by determining their safety in vitro and in vivo in a rat model up to 30 days after administration of a single dose. The in vitro analysis consists of global plasma coagulation (PT, aPTT, and fibrinogen) and platelet aggregation tests while the hematotoxicity studies in vivo include a complete blood count and the possible genotoxic effect analysis in the bone marrow hematopoietic function. Prolonged aPTT values indicate a higher anticoagulant effect for NP-DMSA compared with PEG-coated nanoparticles as a consequence of the higher surface charge of the former. The in vivo tests showed that these bioferrofluids do not cause genotoxic effects, affect erythropoiesis or increase the number of immature erythrocytes in the bone marrow at the analyzed dose. However, nanoparticle administration showed a significant effect on the leukocyte counts in animals treated with DMSA coated nanoparticles 24 h after injection. This response is not observed in animals treated with PEG modified nanoparticles which justifies the use of this polymer in biomasking strategies.L.M.A.A. acknowledges financial support from the Spanish Ministry of Science and Innovation FPI research grants. Technical support from the University Hospital Lozano Blesa, Zaragoza, Spain and from María Angeles Gracia, Ana Isabel Martínez de Ternero, Maria Rosa Borrell Sanz. AR holds a predoctoral fellowship from a CSIC-CITMA collaborative project (B01CU2009; ICMM, 2011–2014) and a short-term fellowship from CNPq (DTI-2; 383934/2013-3). This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (MAT2011-23641 and MAT2011-25991).Peer Reviewe

A DIGE proteomic analysis of wheat flag leaf treated with TERRA-SORB® foliar, a free amino acid high content biostimulant

The flag leaf is the most important source of carbohydrate during wheat kernel filling. Around a 75% of all sugars stored in the kernel come from carbon fixed by this leaf. Terra-Sorb® foliar is an L-α-amino acid-based product from enzymatic hydrolysis for foliar application with a high ratio of free to total amino acids. Previous agronomical studies carried out on grassy, horticultural and tree crops have shown that the application of Terra-Sorb® increases photosynthetic plant activity and chlorophyll content, promotes rapid recovery from stress and improves fruit set. In this work, we have undertaken a proteomic approach to explore molecular mechanisms potentially involved in the stimulating effect of Terra-Sorb® Foliar on wheat yield when applied in commercial fields. Wheat plants at the flag leaf stage were treated, and a DIGE approach was used to compare the proteomes of treated vs. control plants in four biological replicates. Thirty-seven protein spots were found to change in abundance (ANOVA p<0.05) out of which 8 were down-regulated and 29 up-regulated in treated leaves. Twenty protein spots (1.2<fold change <1.9) encoded by 11 different genes were successfully identified by nLC-ESI-MS/MS and NCBInr database search. The deregulated proteins identified were mainly related to the life cycle of Rubisco. Importantly, two proteins involved in the positive regulation of Rubisco activity, namely Rubisco activase, and the large subunit of Rubisco binding protein, were found up-regulated in treated plants, suggesting a better performance of Rubisco. Down-regulated proteins were of metabolic and anti-stress enzymes, including Cu/Zn superoxide dismutase that protects photosystem 11 from photooxidation. In conclusion, significant changes were shown to occur in the wheat flag leaf proteome upon Terra-Sorb® Foliar application. The deregulated proteins identified are directly or indirectly involved in the C02 fixation which may correlate with the known stimulating effect of Terra-Sorb® Foliar of wheat yield, although further functional experiments are needed to validate the proposed hypothesis.This work was supported by Bioibérica, S.A. MJME acknowledged a grant contract from Fundación CajaMurcia-Universidad de Alicante

Development and external validation of a faecal immunochemical test-based prediction model for colorectal cancer detection in symptomatic patients

Background: risk prediction models for colorectal cancer (CRC) detection in symptomatic patients based on available biomarkers may improve CRC diagnosis. Our aim was to develop, compare with the NICE referral criteria and externally validate a CRC prediction model, COLONPREDICT, based on clinical and laboratory variables. Methods: this prospective cross-sectional study included consecutive patients with gastrointestinal symptoms referred for colonoscopy between March 2012 and September 2013 in a derivation cohort and between March 2014 and March 2015 in a validation cohort. In the derivation cohort, we assessed symptoms and the NICE referral criteria, and determined levels of faecal haemoglobin and calprotectin, blood haemoglobin, and serum carcinoembryonic antigen before performing an anorectal examination and a colonoscopy. A multivariate logistic regression analysis was used to develop the model with diagnostic accuracy with CRC detection as the main outcome. Results: we included 1572 patients in the derivation cohort and 1481 in the validation cohorts, with a 13.6 % and 9.1 % CRC prevalence respectively. The final prediction model included 11 variables: age (years) (odds ratio [OR] 1.04, 95 % confidence interval [CI] 1.02-1.06), male gender (OR 2.2, 95 % CI 1.5-3.4), faecal haemoglobin ≥20 μg/g (OR 17.0, 95 % CI 10.0-28.6), blood haemoglobin <10 g/dL (OR 4.8, 95 % CI 2.2-10.3), blood haemoglobin 10-12 g/dL (OR 1.8, 95 % CI 1.1-3.0), carcinoembryonic antigen ≥3 ng/mL (OR 4.5, 95 % CI 3.0-6.8), acetylsalicylic acid treatment (OR 0.4, 95 % CI 0.2-0.7), previous colonoscopy (OR 0.1, 95 % CI 0.06-0.2), rectal mass (OR 14.8, 95 % CI 5.3-41.0), benign anorectal lesion (OR 0.3, 95 % CI 0.2-0.4), rectal bleeding (OR 2.2, 95 % CI 1.4-3.4) and change in bowel habit (OR 1.7, 95 % CI 1.1-2.5). The area under the curve (AUC) was 0.92 (95 % CI 0.91-0.94), higher than the NICE referral criteria (AUC 0.59, 95 % CI 0.55-0.63; p < 0.001). On the basis of the thresholds with 90 % (5.6) and 99 % (3.5) sensitivity, we divided the derivation cohort into three risk groups for CRC detection: high (30.9 % of the cohort, positive predictive value [PPV] 40.7 %, 95 % CI 36.7-45.9 %), intermediate (29.5 %, PPV 4.4 %, 95 % CI 2.8-6.8 %) and low (39.5 %, PPV 0.2 %, 95 % CI 0.0-1.1 %). The discriminatory ability was equivalent in the validation cohort (AUC 0.92, 95 % CI 0.90-0.94; p = 0.7). Conclusions: COLONPREDICT is a highly accurate prediction model for CRC detection

Unveiling the hydrogen bonding network in liquid crystalline natural-based glycosides containing polymeric complexes : experimental and theoretical assessment

This work was supported by the Ministry of Education of Malaysia [FRGS/1/2019/TK05/UITM/02/9, 2019]; Royal Academy of Engineering, U.K., and Academy of Science, Malaysia [NRCP1516/4/61, 2016]; University of Aberdeen [SF10192, 2018] and University Malaya [UMRG grant RP038B-17AFR]. CRediT authorship contribution statement Nurul Fadhilah Kamalul Aripin: Conceptualization, Data curation, Writing - original draft, Writing - review & editing, Funding acquisition. Jonathan Heap: Data curation, Formal analysis. Rafael Piñol: Data curation, Methodology. Vijayan M. Achari: Data curation, Formal analysis, Writing - original draft. Alfonso Martinez-Felipe: Conceptualization, Investigation, Writing - original draft, Writing - review & editing, Funding acquisition.Peer reviewedPostprin

The anti-obesity potential of superparamagnetic iron oxide nanoparticles against high-fat diet-induced obesity in rats: possible involvement of mitochondrial biogenesis in the adipose tissues

Obesity is a pandemic disease that is rapidly growing into a serious health problem and has economic impact on healthcare systems. This bleak image has elicited creative responses, and nanotechnology is a promising approach in obesity treatment. This study aimed to investigate the anti-obesity effect of superparamagnetic iron oxide nanoparticles (SPIONs) on a high-fat-diet rat model of obesity and compared their effect to a traditional anti-obesity drug (orlistat). Methods: The obese rats were treated daily with orlistat and/or SPIONs once per week for 8 weeks. At the end of the experiment, blood samples were collected for biochemical assays. Then, the animals were sacrificed to obtain white adipose tissues (WAT) and brown adipose tissues (BAT) for assessment of the expression of thermogenic genes and mitochondrial DNA copy number (mtDNA-CN). Results: For the first time, we reported promising ameliorating effects of SPIONs treatments against weight gain, hyperglycemia, adiponectin, leptin, and dyslipidemia in obese rats. At the molecular level, surprisingly, SPIONs treatments markedly corrected the disturbed expression and protein content of inflammatory markers and parameters controlling mitochondrial biogenesis and functions in BAT and WAT. Conclusions: SPIONs have a powerful anti-obesity effect by acting as an inducer of WAT browning and activator of BAT functions

Effect of superparamagnetic iron oxide nanoparticles on glucose homeostasis on type 2 diabetes experimental model

[Aims]: Evaluation of the anti-diabetic effect of superparamagnetic iron oxide nanoparticles (SPIONs) on Type 2 diabetic rats and compared their effect to metformin treatment.[Main methods]: Diabetic rats were treated with different doses of nanoparticles one time per week for 4 weeks. Fasting blood glucose level was determined for studied groups during the experimental period (30 days). At the end of the experiment, oral glucose tolerance test was carried out, serum samples were collected for biochemical assays. Then animals were sacrificed to obtain tissues for assessment of glucose transporters, insulin receptors and insulin signaling proteins.[Key finding]: SPIONs treatment normalized fasting blood glucose and lowering insulin level in diabetic rats compared to untreated diabetic rats. SPIONs significantly ameliorate the glucose sensing and the active components of insulin signaling pathway. The anti-diabetic effects of SPIONs may be mediated through its effect on (i) hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha content, which induced by SPIONs treatment in a dose-dependent manner, (ii) adipocytokines as SPIONs treated diabetic rats showed significantly higher levels of adiponectin and lower retinol binding protein 4 compared to untreated diabetic rats, (iii) lipid profile as SPIONs treatment significantly corrected the lipid profile in a dose-dependent manner and to a similar extent as metformin or even better.[Significance]: To our knowledge, this is the first study that explores the anti-diabetic effects of SPIONs on diabetic model.This work was partially supported by the Spanish Ministry of Science, Innovation and Universities (Grant PGC2018-095795-B-I00) and by the European Union's Horizon 2020 FET Open Programme (Grant no. 801305).Peer reviewe

Lanthanide luminescence to mimic molecular logic and computing through physical inputs

The remarkable advances in molecular logic reported in the last decadedemonstrate the potential of luminescent molecules for logical operations, aparadigm-changing concerning silicon-based electronics. Trivalent lanthanide(Ln3+) ions, with their characteristic narrow line emissions, long-lived excitedstates, and photostability under illumination, may improve the state-ofthe-art molecular logical devices. Here, the use of monolithic silicon-basedstructures incorporating Ln3+ complexes for performing logical functions isreported. Elementary logic gates (AND, INH, and DEMUX), sequential logic(KEYPAD LOCK), and arithmetic operations (HALF ADDER and HALF SUBTRACTOR)exhibiting a switching ratio >60% are demonstrated for the firsttime using nonwet conditions. Additionally, this is the first report showingsequential logic and arithmetic operations combining molecular Ln3+ complexesand physical inputs. Contrary to chemical inputs, physical inputs mayenable the future concatenation of distinct logical functions and reuse of thelogical devices, a clear step forward toward input–output homogeneity that isprecluding the integration of nowadays molecular logic devices.</p

Self-assembly of liquid crystal block copolymer PEG-b-smectic polymer in pure state and in dilute aqueous solution

A series of amphiphilic LC block copolymers, in which the hydrophobic block is a smectic polymer poly(4-methoxyphenyl 4-(6-acryloyloxy-hexyloxy)-benzoate) (PA6ester1) and the hydrophilic block is polyethyleneglycol (PEG), were synthesized and characterized. The self-assembly of one of them in both the pure state and the dilute aqueous solution was investigated in detail. Nano-structures in the pure state were studied by SAXS and WAXS on samples aligned by a magnetic field. A hexagonal cylindrical micro-segregation phase was observed with a lattice distance of 11.2 nm. The PEG blocks are in the cylinder, while the smectic polymer blocks form a matrix with layer spacing 2.4 nm and layer normal parallel to the long axis of the cylinders. Faceted unilamellar polymer vesicles, polymersomes, were formed in water, as revealed by cryo-TEM. In the lyotropic bilayer membrane of these polymersomes, the thermotropic smectic order in the hydrophobic block is clearly visible with layer normal parallel to the membrane surface

No Excess Mortality up to 10 Years in Early Stages of Breast Cancer in Women Adherent to Oral Endocrine Therapy: A Probabilistic Graphical Modeling Approach

Breast cancer (BC) is globally the most frequent cancer in women. Adherence to endocrine therapy (ET) in hormone-receptor-positive BC patients is active and voluntary for the first five years after diagnosis. This study examines the impact of adherence to ET on 10-year excess mortality (EM) in patients diagnosed with Stages I to III BC (N = 2297). Since sample size is an issue for estimating age- and stage-specific survival indicators, we developed a method, ComSynSurData, for generating a large synthetic dataset (SynD) through probabilistic graphical modeling of the original cohort. We derived population-based survival indicators using a Bayesian relative survival model fitted to the SynD. Our modeling showed that hormone-receptor-positive BC patients diagnosed beyond 49 years of age at Stage I or beyond 59 years at Stage II do not have 10-year EM if they follow the prescribed ET regimen. This result calls for developing interventions to promote adherence to ET in patients with hormone receptor-positive BC and in turn improving cancer survival. The presented methodology here demonstrates the potential use of probabilistic graphical modeling for generating reliable synthetic datasets for validating population-based survival indicators when sample size is an issue