Tocilizumab as a first-line biologic treatment in rheumatoid arthritis patients – the impact of concomitant methotrexate treatment and Rheumatic Disease Comorbidity Index on the clinical response – results from the multicenter observational ACT-POL study

ObjectivesAccording to the EULAR recommendations, remission or low disease activity (LDA) in rheumatoid arthritis should be achieved by a maximum of 6 months (M6) of treatment. Data on the use of tocilizumab (TCZ) as first-line biologic treatment in rheumatoid arthritis (RA) in routine clinical practice in Poland are lacking.Material and methodsThis multicenter, non-interventional, prospective, observational study recruited adults, presenting with moderate-to-severe RA, showing an inadequate response or intolerance to disease-modifying antirheumatic drugs, where TCZ was the first-line biologic treatment. The effectiveness of TCZ was assessed by the proportion of patients achieving remission and low disease activity following 6 months of treatment with intravenous TCZ. The impact of comorbidities on treatment outcomes was measured using the Rheumatic Disease Comorbidity Index (RDCI).ResultsTotal remission rates at months 3 and 6 were 6% and 31%, respectively. Low disease activity was reported in 10% and 92% of the patients at 3 and 6 months, respectively. The response was comparable between TCZ as monotherapy and in combination with methotrexate. Mean DAS28 decreased from 6.61 at baseline to 4.27 at the scheduled time of the assessment (3 and 6 months). The Rheumatic Disease Comorbidity Index was not correlated with the number of patients achieving LDA at M3 and M6 or remission rates at M6. Remission rates correlated with RDCI at M3. A total of 114 adverse events were reported in 61 patients, among which five were considered as serious.ConclusionsThe study confirms the effectiveness and safety of TCZ in real-world settings as a first-line biologic treatment in patients with moderate-to-severe RA. Importantly, comorbidities do not affect the results of 6-month treatment with TCZ, that is, the optimal time to achieve at least LDA. Our results may improve the effects of RA therapy in Poland, especially in patients with comorbidities and those who, for various reasons, cannot receive optimal treatment with methotrexate.     

Foaming of PCL-Based Composites Using scCO2—Biocompatibility and Evaluation for Biomedical Applications

The process of foaming poly(caprolactone)-based composite materials using supercritical carbon dioxide was analyzed, especially in terms of the biocompatibility of the resultant materials. The influence of foaming process conditions and composite material properties on the functional properties of polymer solid foams, intended for artificial scaffolds for bone cell culture, was investigated. The relationship between wettability (contact angle) and water absorption rate as a result of the application of variable conditions for the production of porous structures was presented. For the evaluation of potential cytotoxicity, the MTT and PrestoBlue tests were carried out, and animal cells (mouse fibroblasts) were cultured on the materials for nine days. There was no toxic effect of composite materials made of poly(caprolactone) containing porogen particles: hydroxyapatite, crystalline nanocellulose, and graphene oxide on cells. The desired effect of the porogens used in the foaming process on the affinity of cells to the resultant material was demonstrated. The tested materials have been shown to be biocompatible and suitable for applications in biomedical engineering.     

The Role of Social Support in Machismo and Acceptance of Violence Among Adolescents in Europe: Lights4Violence Baseline Results

PurposeTo analyze the potential association between social support, experiences of violence, and sociodemographic characteristics of adolescents and the likelihood of acceptance of violence and machismo in different European countries.MethodsCross-sectional design. We recruited 1,555 participants ages 13–16 from secondary schools in Alicante (Spain), Rome (Italy), Iasi (Romania), Matosinhos (Portugal), Poznan (Poland), and Cardiff (UK). We used linear regression models to identify how social support from teachers and parents, experiences of violence—dating violence, bullying, cyberbullying, abuse in childhood—and sociodemographic characteristics were associated with violent thinking, specifically: machismo and acceptance of violence. The analysis was stratified by sex.ResultsAcceptance of violence was higher for those who had lower perceived social support from parents (β_girls = ?154, p < .001; β_boys = ?.114, p = .019) for both sexes. Perpetration of bullying and/or cyberbullying was associated with higher scores for machismo and acceptance of violence for both sexes (β_girls = .067, p = .035; β_boys = .225, p < .001; (β_girls = .118, p < .001; β_boys = .210, p < .001). Being the victim of dating violence, having suffered physical and/or sexual abuse in childhood, and lower perceived social support from teachers were associated with higher scores for both machismo and acceptance of violence. These associations differed between girls and boys.ConclusionsMachismo and acceptance of violence are widely present amongst adolescents in different European countries. Our results suggest the importance of providing educational/psycho-educational interventions with boys and girls to prevent these attitudes and, in turn, prevent interpersonal violence, including bullying and dating violence.     

Angiopoietin-2 as a biomarker of non-ST-segment elevation myocardial infarction in patients with or without type 2 diabetes

IntroductionAngiopoietin-2 (Ang-2) is a novel marker of coronary artery disease (CAD) and diabetes (DM). The aim was to evaluate Ang-2 as a potential new biomarker of non-ST elevation myocardial infarction (NSTEMI) in patients with or without type 2 DM (T2DM).Material and methodsThis was a multi-center, prospective study that included 138 (males: 91/66%) consecutive patients hospitalized due to NSTEMI, T2DM, or different cardiac disorders. The subjects were divided into four study groups: group A: 28 patients with NSTEMI and T2DM; group B: 47 patients with NSTEMI without T2DM; group C: 31 patients with T2DM, without a history of CAD; group D: 32 patients as a control group. Patients with NSTEMI underwent urgent coronarography. Clinical characteristics including biomarkers (hs-CRP, hsTnT, NT-proBNP, VEGF, HbA_1c), SYNTAX SCORE, type of intervention (PCI vs. CABG), and number of implanted stents were taken into account in the analysis.ResultsSerum Ang-2 concentrations were significantly higher in patients with NSTEMI (group A: 1769 pg/ml; group B: 1757 pg/ml) and patients with T2DM (group C: 1993 pg/ml) as compared to the patients without CAD and without T2DM (group D: 866.8 pg/ml; p < 0.05). The prognostic accuracy of Ang-2 in NSTEMI diagnosis was determined with the area under the ROC curve (area under curve (AUC) = 0.63).ConclusionsAngiopoietin-2 serum concentration is elevated in the presence of NSTEMI in patients with and without T2DM and does not correspond to the degree of myocardial injury and hemodynamic status. Ang-2 remains elevated also in patients with T2DM without a history of CAD.     

Antibacterial and Biodegradable Polysaccharide-Based Films for Food Packaging Applications: Comparative Study

One of the major objectives of food industry is to develop low-cost biodegradable food packaging films with optimal physicochemical properties, allowing for their large-scale production and providing a variety of applications. To meet the expectations of food industry, we have fabricated a series of solution-cast films based on common biodegradable polysaccharides (starch, chitosan and alginate) to be used in food packaging applications. Selected biopolymers were modified by the addition of glycerol and oxidized sucrose (starch), glycerol (chitosan), and glycerol and calcium chloride (alginate), as well as being used to form blends (starch/chitosan and starch/alginate, respectively). A chestnut extract was used to provide antibacterial properties to the preformed materials. The results of our studies showed that each modification reduced the hydrophilic nature of the polymers, making them more suitable for food packaging applications. In addition, all films exhibited much higher barrier properties to oxygen and carbon dioxide than commercially available films, such as polylactic acid, as well as exhibiting antimicrobial properties against model Gram-negative and Gram-positive bacteria (Escherichia coli and Staphylococcus epidermidis, respectively), as well as yeast (Candida albicans).     

Acoustic Performance of Sound Absorbing Materials Produced from Wool of Local Mountain Sheep

Wool of mountain sheep, treated nowadays as a waste or troublesome byproduct of sheep husbandry, was used for the production of sound-absorbing materials. Felts of two different thicknesses were produced from loose fibres. Additionally, two types of yarn, ring spun and core rug, were obtained. The yarns were used for the production of tufted fabric with cut and loop piles. During the examinations, basic parameters of the obtained materials were determined. Then, according to standard procedure with the use of impedance tube, the sound absorption coefficient was measured, and the noise reduction coefficient (NRC) was calculated. It was revealed that felt produced from coarse wool exhibits high porosity, and its sound absorbing capacity is strongly related to the felt thickness. For thicker felt the NRC achieved 0.4, which is comparable with the NRC of commercial ceiling tiles. It was shown that the crucial parameter influencing the sound absorption of the tufted fabrics was the pile height. For both types of yarns, when the height of the pile was increased from 12 to 16 mm, the NRC increased from 0.4 to 0.42. The manufactured materials made from local wool possess good absorption capacity, similar to commercial products usually made from more expensive wool types. The materials look nice and can be used for noise reduction as inner acoustic screens, panels, or carpets.     

Stereoselective Synthesis and Anticancer Activity of 2,6-Disubstituted trans-3-Methylidenetetrahydropyran-4-ones

In this report, we present efficient and stereoselective syntheses of 2,6-disubstituted trans-3-methylidenetetrahydropyran-4-ones and 2-(4-methoxyphenyl)-5-methylidenetetrahydropyran-4-one that significantly broaden the spectrum of the available methylidenetetrahydropyran-4-ones with various substitution patterns. Target compounds were obtained using Horner–Wadsworth–Emmons methodology for the introduction of methylidene group onto the pyranone ring. 3-Diethoxyphosphoryltetrahydropyran-4-ones, which were key intermediates in this synthesis, were prepared by fully or highly stereoselective addition of Gilman or Grignard reagents to 3-diethoxyphosphoryldihydropyran-4-ones. Addition occurred preferentially by axial attack of the Michael donors on the dihydropyranone ring. Relative configurations and conformations of the obtained adducts were assigned using a detailed analysis of the NMR spectra. The obtained methylidenepyran-4-ones were evaluated for cytotoxic activity against two cancer cell lines (HL-60 and MCF-7). 2,6-Disubstituted 3-methylidenetetrahydropyran-4-ones with isopropyl and phenyl substituents in position 2 were more cytotoxic than analogs with n-butyl substituent. Two of the most cytotoxic analogs were then selected for further investigation on the HL-60 cell line. Both analogs induced morphological changes characteristic of apoptosis in cancer cells, significantly inhibited proliferation and induced apoptotic cell death. Both compounds also generated DNA damage, and one of the analogs arrested the cell cycle of HL-60 cells in the G2/M phase. In addition, both analogs were able to inhibit the activity of topoisomerase IIα. Based on these findings, the investigated analogs may be further optimized for the development of new and effective topoisomerase II inhibitors.     

Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.MethodsA multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).ResultsMHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical “micro-FAFs”) in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.ConclusionTSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.FundingThis work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program).     

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial.Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm.Results For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08–0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24–1.81) (P-interaction = 0.17).Conclusion Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.Subject terms: Breast cancer, Translational research, Predictive markers, Breast cancer