The interferon-induced helicase C domain-containing protein 1 gene variant (rs1990760) as an autoimmune-based pathology susceptibility factor

PurposeAutoimmune diseases are a group of complex diseases localized in multiple organ systems, with a wide spectrum of symptoms and still unclear causes. The aim of the present study was to analyse a possible association of three autoimmune disabilities - Multiple sclerosis (MS), LADA diabetes and Graves’ disease (GD) with single nucleotide polymorphism (SNP; rs1990760) in the IF IH1 gene (also known as a melanoma differentiation-associated protein 5 - MDA5) within the Polish population. An additional goal was also to look for a correlation between this polymorphism and different clinical patient-related factors.Materials and methodsThe study population consisted of four groups of 944 unrelated Polish origin Caucasian patients – 324 with GD, 171 with MS, 49 with LADA diabetes and 400 healthy subjects as a control group. The SNP analysis was performed using the allelic discrimination technique.Results & ConclusionsThere were significant associations of risk T allel of the analyzed polymorphism with all studied autoimmune diseases (GDOR = 1.34, p = 7.02e-03; MSOR = 1.36, p = 2.17e-02; LADA – OR = 3.36, p = 8.73e-07). We also found that the frequency of CT and TT genotypes of the rs1990760 IFIH1 gene only in females (with LADA, GD, MS) was significantly higher than those in the female control group (47%, 41% vs 44%, 34%; p = 1.32e-03, p = 4.39e-04; OR = 2.08, 95%CI: (1.33–3.28), OR = 2.29, 95% CI: (1.44–3.65) respectively). Our research has shown significant differences regarding some clinical features (BMI, TRAb, TSH, HbA1C, anti-GAD antibodies) and age at the beginning of the studied autoimmune disabilities. This study showed an association of rs1990760 polymorphism in the IFIH1 gene in the development of GD, LADA diabetes and MS within the Polish population. To our knowledge, this is the first study to investigate the relationship between IFIH1 polymorphisms and the risk of the development of MS and LADA in Poland.     

Efficacy of daratumumab monotherapy in real-world heavily pretreated patients with relapsed or refractory multiple myeloma

PurposeDaratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting.Patients and methodsThirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DRMM) were included to the Polish Myeloma Group observational study.ResultsThe objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events.ConclusionDaratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.     

Characterization of aqueous interactions of copper-doped phosphate-based glasses by vapour sorption

Owing to their adjustable dissolution properties, phosphate-based glasses (PGs) are promising materials for the controlled release of bioinorganics, such as copper ions. This study describes a vapour sorption method that allowed for the investigation of the kinetics and mechanisms of aqueous interactions of PGs of the formulation 50P₂O₅–30CaO–(20–x)Na₂O–xCuO (x = 0, 1, 5 and 10 mol.%). Initial characterization was performed using ³¹P magic angle spinning nuclear magnetic resonance and attenuated total reflectance–Fourier transform infrared spectroscopy. Increasing CuO content resulted in chemical shifts of the predominant Q² NMR peak and of the (POP)_as and (PO⁻) Fourier transform infrared absorptions, owing to the higher strength of the POCu bond compared to PONa. Vapour sorption and desorption were gravimetrically measured in PG powders exposed to variable relative humidity (RH). Sorption was negligible below 70% RH and increased exponentially with RH from 70 to 90%, where it exhibited a negative correlation with CuO content. Vapour sorption in 0% and 1% CuO glasses resulted in phosphate chain hydration and hydrolysis, as evidenced by protonated Q⁰(1H) and Q¹(1H) species. Dissolution rates in deionized water showed a linear correlation (R² > 0.99) with vapour sorption. Furthermore, cation release rates could be predicted based on dissolution rates and PG composition. The release of orthophosphate and short polyphosphate species corroborates the action of hydrolysis and was correlated with pH changes. In conclusion, the agreement between vapour sorption and routine characterization techniques in water demonstrates the potential of this method for the study of PG aqueous reactions.     

In situ characterization of change in superficial organic components of thermoacidophilic archaeon Acidianus manzaensis YN-25

For the first time, synchrotron radiation (SR) -based carbon K-edge X-ray absorption near edge structure (XANES) spectroscopy in-situ characterization was conducted to evaluate the evolution of superficial (about 10 nm) organic components of extracellular polymeric substances (EPS) of thermoacidophilic archaeon Acidianus manzaensis YN-25 acclimated with different energy substrates (FeS₂, CuFeS₂, S⁰, FeSO₄). The atomic force microscopy (AFM) morphology scanning showed that the strain acclimated with different energy substrates varied a lot in EPS amount. XANES results showed clear associations between the energy substrates and the changes in organic composition in terms of typical function groups (CO, CO and CN). The chalcopyrite- and pyrite-acclimated cells contained higher proportion of proteins but less proportion of polysaccharides than the S⁰-acclimated cells. The FeSO₄-acclimated cells contained the highest proportion of proteins, while the S⁰-acclimated cells contained more lipids and polysaccharides. The results of linear-combination and peak fitting of the K-edge XANES for the extracellular superficial organic component C is consistent with the trend in comparison with the results of FTIR and spectrophotometric determination, but there are significant differences in the values. These differences are caused by the inconsistencies of measurement depth between XANES and the latter two characterization methods.     

Fluorescence,aggregation properties and FT-IR microspectroscopy of elastin and collagen fibers

Histological and histochemical observations support the hypothesis that collagen fibers can link to elastic fibers. However, the resulting organization of elastin and collagen type complexes and differences between these materials in terms of macromolecular orientation and frequencies of their chemical vibrational groups have not yet been solved. This study aimed to investigate the macromolecular organization of pure elastin, collagen type I and elastin–collagen complexes using polarized light DIC-microscopy. Additionally, differences and similarities between pure elastin and collagen bundles (CB) were investigated by Fourier transform-infrared (FT-IR) microspectroscopy. Although elastin exhibited a faint birefringence, the elastin–collagen complex aggregates formed in solution exhibited a deep birefringence and formation of an ordered-supramolecular complex typical of collagen chiral structure. The FT-IR study revealed elastin and CB peptide NH groups involved in different types of H-bonding. More energy is absorbed in the vibrational transitions corresponding to CH, CH₂ and CH₃ groups (probably associated with the hydrophobicity demonstrated by 8-anilino-1-naphtalene sulfonic acid sodium salt [ANS] fluorescence), and to νCN, δNH and ωCH₂ groups of elastin compared to CB. It is assumed that the α-helix contribution to the pure elastin amide I profile is 46.8%, whereas that of the B-sheet is 20% and that unordered structures contribute to the remaining percentage. An FT-IR profile library reveals that the elastin signature within the 1360–1189 cm⁻¹ spectral range resembles that of Conex–Toray aramid fibers.     

Poly(vinyl alcohol) microspheres with pH- and thermosensitive properties as temperature-controlled drug delivery

One of the most important inconveniences of the pH- and temperature-sensitive hydrogels is the loss of thermosensitivity when relatively large amounts of a pH-sensitive monomer are co-polymerized with N-isopropylacrylamide (NIPAAm). In order to overcome this drawback, we propose here a method to prepare thermosensitive poly(vinyl alcohol) (PVA) microspheres with a higher content of carboxylic groups that preserve thermosensitive properties. Moreover, PVA possesses excellent mechanical properties, biocompatibility and non-toxicity. PVA microspheres were obtained by suspension cross-linking of an acidified aqueous solution of the polymer with glutaraldehyde. Poly(N-isopropylacrylamide-co-N-hydroxymethyl acrylamide) (poly(NIPAAm-co-HMAAm)), designed to have a lower critical solution temperature (LCST) corresponding to that of the human body, was grafted onto PVA microspheres in order to confer them with thermosensitivity. Then, the pH-sensitive functional groups (COOH) were introduced by reaction between the un-grafted OH groups of PVA and succinic anhydride. The pH- and temperature-sensitive PVA microspheres display a sharp volume transition under physiological conditions around the LCST of the linear polymer. The microspheres possess good drug-loading capacity without losing their thermosensitive properties. Under simulated physiological conditions, the release of drugs is controlled by temperature.     

Rat calvaria osteoblast behavior and antibacterial properties of O2 and N2 plasma-implanted biodegradable poly(butylene succinate)

Poly(butylene succinate), a novel biodegradable aliphatic polyester with excellent processability and mechanical properties, was modified by O₂ or N₂ plasma immersion ion implantation (PIII). X-ray photoelectron spectroscopy and contact angle measurements were carried out to reveal the surface characteristics of the treated and control specimens. The in vitro effects of the materials on seeded osteoblasts were detected by cell viability assay, alkaline phosphatase activity test, and real-time polymerase chain reaction analysis. Plate counting was performed to investigate the antibacterial properties. Our results show that both PIII treatments significantly improve the hydrophilicity of PBSu, and CO and nitrogen groups (CNH and CNH₂) can be detected on the PBSu after O₂ and N₂ PIII, respectively. The modified samples exhibit similar compatibility to osteoblasts, which is better than that of the control, but O₂ PIII and N₂ PIII produce different effects according to the osteogenic gene expressions of seeded osteoblasts on the materials. Moreover, the N₂ plasma-modified PBSu exhibits anti-infection effects against Staphylococcus aureus and Escherichia coli but no such effects can be achieved after O₂ PIII.     

Surface modification of poly(ε-caprolactone) using a dielectric barrier discharge in atmospheric pressure glow discharge mode

The role of roughening and functionalization processes involved in modifying the wettability of poly(ε-caprolactone) (PCL) after treatment by an atmospheric pressure glow discharge plasma is discussed. The change in the ratio of CO/C–O bonds is a significant factor influencing the wettability of PCL. As the contact angle decreases, the level of CO bonds tends to rise. Surface roughness alterations are the driving force for lasting increases in wettability, while the surface functional species are shorter lived. We can approximate from ageing that the increase in wettability for PCL after plasma treatment is 55–60% due to roughening and 40–45% due to surface functionalization for the plasma device investigated.     

Selectivity of binding of PEGs and PEG-like oligomers to anti-PEG antibodies induced by methoxyPEG-proteins

The use of methoxypoly(ethylene glycol) (mPEG) in PEG conjugates of proteins and non-protein therapeutic agents has led to the recognition that the polymer components of such conjugates can induce anti-PEG antibodies (anti-PEGs) that may accelerate the clearance and reduce the efficacy of the conjugates. Others have classified anti-PEGs as “methoxy-specific” or “backbone-specific”. The results of our previous research on anti-PEGs in the sera of rabbits immunized with mPEG or hydroxyPEG (HO-PEG) conjugates of three unrelated proteins were consistent with that classification (Sherman, M.R., et al., 2012. Bioconjug. Chem. 23, 485–499). Enzyme-linked immunosorbent assays (ELISAs) were performed on rabbit antisera and rabbit monoclonal anti-PEGs with competitors including 10 kDa mPEG, 10 kDa PEG diol and six linear or cyclic oligomers of oxyethylene (CH₂CH₂O), with molecular weights of ca. 150–264 Da. Our results demonstrate that (1) the binding affinities of anti-mPEGs depend more on the backbone lengths of the polymers and the hydrophobicities of their end-groups than on their resemblance to the methoxy terminus of the immunogenic polymer; (2) anti-PEGs raised against HO-PEG-proteins are not directed against the terminal hydroxy group, but against the backbone; (3) rabbit anti-PEGs bind to and distinguish among PEG-like oligomers with as few as three oxyethylene groups; and (4) none of the monoclonal or polyclonal anti-PEGs was absolutely “methoxy-specific” or “backbone-specific”, but displayed distinct relative selectivities. If these results are relevant to human immune responses, the clinical use of stable conjugates of HO-PEG with proteins and non-protein therapeutic agents would be expected to produce fewer and less intense immune responses than those induced by conjugates with mPEG or PEGs with larger alkoxy groups.     

Magnesium isoglycyrrhizinate alleviates liver injury in obese rats with acute necrotizing pancreatitis

Objective

For patients with acute necrotizing pancreatitis (ANP), a high body mass index (BMI) increases the likelihood of acute hepatic injury (AHI). In the current study, we explored whether magnesium isoglycyrrhizinate (MgIg) could alleviate ANP-induced liver injury in obese rats.

Anti-genotoxic effect of the Sargassum dentifolium extracts: Prevention of chromosomal aberrations,micronuclei, and DNA fragmentation

The alga Sargassum dentifolium (Turner) C. Agardh, belongs to Sargassaceae, is a brown seaweed in red sea shores in Egypt. This work aimed to extract different water-soluble polysaccharide extracts (E1, E2, and E3) from S. dentifolium and to investigate their protective effect against cyclophosphamide (CP)-induced genotoxicity. Mice bone marrow cells (BMCs) were collected and analyzed for the chromosomal aberration, micronucleated BMCs (MN-BMCs), the mitotic index, DNA fragmentation by comet assay, and histone deacetylases (HDACs), and radical scavenging capacity of extracts was evaluated by the oxygen radical absorbance capacity assay.The results indicated that E2 and E3 significantly inhibited CP-induced multiple chromosomal aberrations, where E1 and E3 significantly suppressed the number of CP-induced formation of tetraploidy. The extracts prohibited the cytotoxic effect of CP and recovered the mitotic activity, whereas E1 possessed the highest recovery and mitosis. In absence of MN, CP induced formation of bi- and poly-nucleated BMCs. E1 prohibited CP-induced formation of bi-nucleated BMCs, while E2 and E3 prohibited CP-induced formation of poly-nucleated BMCs. CP-induced MN-BMCs were accompanied with mono-, bi- and poly-nucleated cells. E1 and E3 remarkably suppressed mono-nucleated MN-BMCs, while E2 inhibited bi-nucleated MN-BMCs. All the extracts significantly inhibited the CP-induced formation of poly-nucleated MN-BMCs. CP-induced DNA fragmentation was inhibited by all extracts, where E1 was the strongest inhibitor as concluded from the comet tail moment. All the extracts were strong OH scavengers, while only E3 was ROO scavenger. The results revealed a drastic decline in HDACs activity by E1 and E3. In conclusion, S. dentifolium polysaccharide extracts E1 and E3 possessed a potential anti-genotoxic and a promising anti-mutagenic activity.     

Intracellular chromosome breaks on silicon surface

The genotoxicity of silicon (Si) is investigated by soaking crystalline Si in a complete culture medium for 60 days and conducting micronuclei tests (MNTs) utilizing hamster ovary (CHO) cells and its Ku80 deficient CHO mutant (xrs5) cells (DNA double-strand breaks repair deficiency). The intracellular concentrations of reactive oxygen/nitrogen species (ROS/RNS) on Si are determined to elucidate the relationship between ROS/RNS and Si-induced genotoxicity by using CHO cells. The cells are treated with ROS scavenger (dimethyl sulfoxide) and MNT are performed. The results indicate that the intracellular concentration of ROS and nitrogen oxide (NO) on Si is higher than those on the control group by about 38% and 12%. ROS/RNS include superoxide (O₂^?) anion, NO, and peroxynitrite (ONOO^?) which can injure chromosomes and induce high cellular DNA double-strand breaks (DSBs).     

Radical scavenging abilities and hepatoprotective effect of [N,N′-Bis (salicylidene) ethane-1, 2-diaminato] oxovanadium (IV) complex in CCl4-treated rats

The antioxidant activity of [N, N′-Bis (salicylidene) ethane-1, 2-diaminato] oxovanadium (IV) complex (VO-salen complex) was evaluated using different in vitro evaluating systems including superoxide anion (O₂^?) and hydrogen peroxide (H₂O₂) scavenging activities. In addition, the inhibitory effects of this compound on protein oxidation and inhibition of Fe²⁺/ascorbate-induced lipid peroxidation were studied using rat liver homogenate. In vitro results revealed that the VO-salen complex has strong inhibitory effects on protein oxidation and lipid peroxidation of the liver homogenate along with a concentration-dependent quenching of H₂O₂ and O₂^? radicals. In an in vivo approach, hepatoprotective potential of the VO-salen complex against liver damages induced by CCl₄ treatment was also investigated. After intraperitoneal injection of CCl₄ to rats, various biochemical changes associated with liver injury and/or oxidative stress were measured. The results showed that the sera levels of ALT, AST, ALP and the content of hepatic thiobarbituric acid reactive substances (TBARS) were all increased and the glutathione (GSH) content and the hepatic superoxide dismutase (SOD) and catalase (CAT) activities were decreased in CCl₄-treated rats. However, simultaneous treatment of rats with VO-salen (0.6 mg/kg) and CCl₄ significantly attenuated the sera levels of ALT, AST, ALP and the hepatic TBARS content. In addition, by VO-salen therapy, the hepatic SOD and CAT activities and the GSH content were all restored back almost to their normal levels. The liver damages were also significantly ameliorated as compared to the CCl₄-treated rats. Based on these results, the VO-salen complex might be considered as an effective antioxidant and hepatoprotective agent suitable for further biological evaluation.     

Tunable drug-loading capability of chitosan hydrogels with varied network architectures

Advanced bioactive systems with defined macroscopic properties and spatio-temporal sequestration of extracellular biomacromolecules are highly desirable for next generation therapeutics. Here, chitosan (CT) hydrogels were prepared with neutral or negatively charged cross-linkers in order to promote selective electrostatic complexation with charged drugs. CT was functionalized with varied dicarboxylic acids, such as tartaric acid, poly(ethylene glycol) bis(carboxymethyl) ether, 1,4-phenylenediacetic acid and 5-sulfoisophthalic acid monosodium salt (PhS), whereby PhS was hypothesized to act as a simple mimetic of heparin. Attenuated total reflectance Fourier transform infrared spectroscopy showed the presence of CO amide I, N–H amide II and CO ester bands, providing evidence of covalent network formation. The cross-linker content was reversely quantified by proton nuclear magnetic resonance on partially degraded network oligomers, so that 18 mol.% PhS was exemplarily determined. Swellability (SR: 299 ± 65–1054 ± 121 wt.%), compressibility (E: 2.1 ± 0.9–9.2 ± 2.3 kPa), material morphology and drug-loading capability were successfully adjusted based on the selected network architecture. Here, hydrogel incubation with model drugs of varied electrostatic charge, i.e. allura red (AR, doubly negatively charged), methyl orange (MO, negatively charged) or methylene blue (MB, positively charged), resulted in direct hydrogel–dye electrostatic complexation. Importantly, the cationic compound, MB, showed different incorporation behaviours, depending on the electrostatic character of the selected cross-linker. In light of this tunable drug-loading capability, these CT hydrogels would be highly attractive as drug reservoirs towards e.g. the fabrication of tissue models in vitro.     

Absorbances of hematoxylin solutions at varying pH levels.

An alum hematoxylin was prepared (0.5 g hematoxylin, 8 g potassium alum, distilled water 477.5 ml and Na10(3) solution, 1 mg/ml, 22.5 ml) and divided into 50 ml aliquots. The pH of these aliquots was adjusted with 2 1/2% NaOH or 10% H2SO4. As soon as the pH of a sample was adjusted the absorbance from 400 to 700 nm was recorded with a Cary 15 spectrophotometer using specially designed cuvettes and undiluted samples. The following day the absorbances at peak were measured on a Coleman Jr. spectrophotometer and three days later a variety of tissues was stained with each solution. The pH and peak of absorbance of the aliquots were pH = 2.0 450 NM, 2.5 505, 2.6 507, 2.7 515, 2.8 520, 2.9 530, 3.0 540, 3.1 550, 3.3 560, 3.5 560. In the stained material in the intensity of nuclear staining was about the same at all pH levels but non-specific staining was greatest in slides stained at pH = .5 and virtually absent in slides stained at pH = 2.0. At intermediate pH levels the amount of non-specific staining was intermediate.     

Triggered release of insulin from glucose-sensitive enzyme multilayer shells

A glucose-sensitive multilayer shell, which was fabricated by the layer-by-layer (LbL) assembly method, can be used as a carrier for the encapsulation and controlled release of insulin. In the present report, glucose oxidase (GOD) and catalase (CAT) were assembled on insulin particles alternately via glutaraldehyde (GA) cross-linking. The resulting core–shell system has been proven to be glucose-sensitive. When the external glucose was introduced, the release ratio of insulin from the protein multilayer can be increased observably. This is likely attributed to the catalysis interaction of CAT/GOD shells to glucose, which leads to the production of H⁺ and thus drops the pH of the microenvironment. Under the acidic conditions, on the one hand, a part of CN bond formed from Schiff base reaction can be broken and thus increasing the permeability of the capsule wall. On the other hand, the solubility of insulin can also be increased. The above factors may be the key control to increase the release of insulin from the multilayer. Therefore, such CAT/GOD multilayer may have a great potential as a glucose-sensitive release carrier for insulin, and may open the way for the further application of LbL capsules in the drug delivery and controlled release, etc.     

Healthy conversation skills as an intervention to support healthy gestational weight gain: Experience and perceptions from intervention deliverers and participants

Objective

In a pilot RCT we assessed training a dietitian in “Healthy Conversation Skills” (HCS) to support behavior change. This study describes the acceptability of the intervention from the participant and practitioner perspective.

Efficacy and safety of calcium,magnesium, potassium,and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled,double-blind,randomized withdrawal study in adults with narcolepsy with cataplexy

Study ObjectivesEvaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB).MethodsAdults aged 18–70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment.ResultsEfficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (−0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (−1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%).ConclusionsEfficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB.Clinical trial registration{"type":"clinical-trial","attrs":{"text":"NCT03030599","term_id":"NCT03030599"}}NCT03030599.