The potential of a data centred approach & knowledge graph data representation in chemical safety and drug design

Big Data pervades nearly all areas of life sciences, yet the analysis of large integrated data sets remains a major challenge. Moreover, the field of life sciences is highly fragmented and, consequently, so is its data, knowledge, and standards. This, in turn, makes integrated data analysis and knowledge gathering across sub-fields a demanding task. At the same time, the integration of various research angles and data types is crucial for modelling the complexity of organisms and biological processes in a holistic manner. This is especially valid in the context of drug development and chemical safety assessment where computational methods can provide solutions for the urgent need of fast, effective, and sustainable approaches. At the same time, such computational methods require the development of methodologies suitable for an inte-grated and data centred Big Data view. Here we discuss Knowledge Graphs (KG) as a solution to a data centred analysis approach for drug and chemical development and safety assessment. KGs are knowledge bases, data analysis engines, and knowledge discovery systems all in one, allowing them to be used from simple data retrieval, over meta-analysis to complex predictive and knowledge discovery systems. Therefore, KGs have immense potential to advance the data centred approach, the re-usability, and infor-mativity of data. Furthermore, they can improve the power of analysis, and the complexity of modelled processes, all while providing knowledge in a natively human understandable network data model. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).Peer reviewe

The prismatic Sigma 3 (10-10) twin bounday in alpha-Al2O3 investigated by density functional theory and transmission electron microscopy

The microscopic structure of a prismatic $\Sigma 3$ $(10\bar{1}0)$ twin boundary in \aal2o3 is characterized theoretically by ab-initio local-density-functional theory, and experimentally by spatial-resolution electron energy-loss spectroscopy in a scanning transmission electron microscope (STEM), measuring energy-loss near-edge structures (ELNES) of the oxygen $K$-ionization edge. Theoretically, two distinct microscopic variants for this twin interface with low interface energies are derived and analysed. Experimentally, it is demonstrated that the spatial and energetical resolutions of present high-performance STEM instruments are insufficient to discriminate the subtle differences of the two proposed interface variants. It is predicted that for the currently developed next generation of analytical electron microscopes the prismatic twin interface will provide a promising benchmark case to demonstrate the achievement of ELNES with spatial resolution of individual atom columns

The relationship between particle morphology and rheological properties in injectable nano-hydroxyapatite bone graft substitutes

Biomaterials composed of hydroxyapatite (HA) are currently used for the treatment of bone defects resulting from trauma or surgery. However, hydroxyapatite supplied in the form of a paste is considered a very convenient medical device compared to the materials where HA powder and liquid need to be mixed immediately prior to the bone treatment during surgery. In this study we have tested a series of hydroxyapatite (HA) pastes with varying microstructure and different rheological behaviour to evaluate their injectability and biocompatibility. The particle morphology and chemical composition were evaluated using HRTEM, XRD and FTIR. Two paste-types were compared, with the HA particles of both types being rod shaped with a range of sizes between 20 and 80 nm while differing in the particle aspect ratio and the degree of roundness or sharpness. The pastes were composed of pure HA phase with low crystallinity. The rheological properties were evaluated and it was determined that the pastes behaved as shear-thinning, non-Newtonian liquids. The difference in viscosity and yield stress between the two pastes was investigated. Surprisingly, mixing of these pastes at different ratios did not alter viscosity in a linear manner, providing an opportunity to produce a specific viscosity by mixing the two materials with different characteristics. Biocompatibility studies suggested that there was no difference in vitro cell response to either paste for primary osteoblasts, bone marrow mesenchymal stromal cells, osteoblast-like cells, and fibroblast-like cells. This class of nanostructured biomaterial has significant potential for use as an injectable bone graft substitute where the properties may be tailored for different clinical indications

Electron irradiation induced nanocrystal formation in Cu-borosilicate glass

Nanoscale writing of Cu nanoparticles in glasses is introduced using focused electron irradiation by transmission electron microscopy. Two types of copper borosilicate glasses, one with high and another with low Cu loading, have been tested at energies of 200–300 keV, and formation of Cu nanoparticles in a variety of shapes and sizes using different irradiation conditions is achieved. Electron energy loss spectroscopy analysis, combined with high-resolution transmission electron microscopy imaging, confirmed the irradiation-induced precipitated nanoparticles as metallic, while furnace annealing of the glass triggered dendrite-shaped particles of copper oxide. Unusual patterns of nanoparticle rings and chains under focused electron beam irradiation are also presented. Conclusively, electron beam patterning of Cu-loaded glasses is a promising alternative route to well-established femtosecond laser photoreduction of Cu ions in glass

Dose-dense adjuvant chemotherapy for primary breast cancer

Adjuvant chemotherapy has been proven to reduce significantly the risk for relapse and death in women with operable breast cancer. Nevertheless, the prognosis for patients presenting with extensive axillary lymph node involvement remains suboptimal. In an attempt to improve on the efficacy of existing chemotherapy, a phase III intergroup trial led by the Cancer and Leukemia Group B (CALGB 97-41) was designed, which tested a mathematical model of tumor growth based on the Norton–Simon hypothesis. This hypothesis, developed about 3 decades ago, and the kinetic model derived from it, created the basis of the concepts of dose density and sequential therapy, both of which were tested in CALGB 97-41. This large prospective randomized trial demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose size resulted in significant improvements in disease-free and overall survival in patients with node-positive breast carcinoma. This finding is highly relevant and has immediate implications for clinical practice

14th St. Gallen International Breast Cancer Conference 2015: Evidence, Controversies, Consensus - Primary Therapy of Early Breast Cancer: Opinions Expressed by German Experts

The key topics of this year's 14th St. Gallen Consensus Conference on the diagnosis and therapy of primary breast cancer were again questions about breast surgery and axillary surgery, radio-oncology and systemic therapy options in consideration of tumor biology, and the clinical application of multigene assays. This year, the consensus conference took place in Vienna. From a German perspective, it makes sense to substantiate the results of the vote of the international panel representing 19 countries in light of the updated national therapy recommendations of the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie). Therefore, 14 German breast cancer experts, 3 of whom are members of the International St. Gallen Panel, have commented on the voting results of the St. Gallen Consensus Conference 2015 in relation to clinical routine in Germany

Final results of a phase I/II pilot study of capecitabine with or without vinorelbine after sequential dose-dense epirubicin and paclitaxel in high-risk early breast cancer

Background: The integration of the non-cross-resistant chemotherapeutic agents capecitabine and vinorelbine into an intensified dose-dense sequential anthracycline- and taxane-containing regimen in high-risk early breast cancer (EBC) could improve efficacy, but this combination was not examined in this context so far. Methods: Patients with stage II/IIIA EBC (four or more positive lymph nodes) received post-operative intensified dose-dense sequential epirubicin (150mg/m2 every 2 weeks) and paclitaxel (225mg/m2 every 2 weeks) with filgrastim and darbepoetin alfa, followed by capecitabine alone (dose levels 1 and 3) or with vinorelbine (dose levels 2 and 4). Capecitabine was given on days 1-14 every 21 days at 1000 or 1250 mg/m2 twice daily (dose levels 1/2 and 3/4, respectively). Vinorelbine 25 mg/m2 was given on days 1 and 8 of each 21-day course (dose levels 2 and 4). Results: Fifty-one patients were treated. There was one dose-limiting toxicity (DLT) at dose level 1. At dose level 2 (capecitabine and vinorelbine), five of 10 patients experienced DLTs. Therefore evaluation of vinorelbine was abandoned and dose level 3 (capecitabine monotherapy) was expanded. Hand-foot syndrome and diarrhoea were dose limiting with capecitabine 1250 mg/m2 twice daily. At 35.2 months' median follow-up, the estimated 3-year relapse-free and overall survival rates were 82% and 91%, respectively. Administration of capecitabine monotherapy after sequential dose-dense epirubicin and paclitaxel is feasible in node-positive EBC, while the combination of capecitabine and vinorelbine as used here caused more DLTs. Trial registration: Current Controlled Trials ISRCTN38983527

Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: a meta-analysis

To assess the early effect of epoetin beta on survival and tumour progression in anaemic patients with cancer, data were pooled from nine randomised clinical trials comparing epoetin beta with placebo or standard care. Studies were not primarily designed to assess these end points. Follow-up was for treatment duration plus 4 weeks following therapy completion. All adverse events (AEs) were retrospectively reviewed blinded, for progression. Thromboembolic events were also assessed. Data analysis involved standard statistical tests. Overall, 1413 patients were included (epoetin beta, n=800; control, n=613; 56% haematological, and 44% solid). Median initial epoetin beta dose was 30 000 IU/week. Overall survival during months 0–6 was similar with epoetin beta and control (0.31 vs 0.32 deaths/patient-year). No increased mortality risk was seen with epoetin beta (relative risk (RR) 0.97, 95% CI: 0.69, 1.36; P=0.87). There was a significantly reduced risk of rapidly progressive disease for epoetin beta (RR 0.78, 95% CI: 0.62, 0.99; P=0.042). Epoetin beta was associated with a slightly higher frequency of thromboembolic events vs control (5.9% vs 4.2% of patients) but thromboembolic-related mortality was identical in both groups (1.1%). Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic-related mortality

Effects of the latest drought on the alluvial aquifer of a semiarid region in northeastern Brazil

Climate change has modified global and local water cycle patterns inducing more intense and severe drought events. In the Ceará state (Northeast Brazil), a semiarid region very vulnerable to droughts, groundwater acts as a strategic reserve to ensure water security for small rural communities. Well drilling jointly with the building of dams and cisterns are the main policy performed by the public authority to cope with the droughts. This study performed a preliminary qualitative analysis to investigate the effects of dam building in the piezometric level of an alluvial aquifer in the Ceará state during the most recent drought (2012–2016). The micro-basins of the Algodão and Forquilha creek were selected as study area, in which the alluvial aquifer has been monitored by Funceme since 2010. The alluvial aquifer was extensively exploited for local agriculture before the drought (2012–2016) due to public policies of well drilling (2001–2002). During the most recent drought, the construction of new dams, coupled with reduced rainfall, compromised the recharge of the alluvial aquifer. We evaluate these effects through the groundwater level. The results revealed a continuous drawdown of groundwater in the monitored wells. Since 2017 the piezometric level started to rise, however, the graphs reveal a different behavior of the piezometric levels monitored after the latest drought, with sudden changes between the periods of recharge and drawdown of the alluvial aquifer. Field diagnostics with local stakeholders revealed how the latest drought changed the dynamics of the activities developed by the rural communities. Before the drought the aquifer supplied the local agriculture. The drought has affected the recharge of the alluvial aquifer and compromised local agriculture. Local stakeholders have adapted, and agriculture has been replaced by livestock. The heterogeneity of this environment and of its water users requires efficient management policies adapted for the local physical and socioeconomic conditions to avoid overexploitation and maintain the recharge of the alluvial aquifer. These policies at the local scale can be the identification of local actors who are willing to develop their own management of surface and groundwater resources.</p