bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of bevacizumab in first- and second-line treatment for metastatic colorectal cancer: ITACa randomized trial
Authors: Petracci Elisabetta , Scarpi Emanuela , Passardi Alessandro , Biggeri Annibale , Milandri Carlo , Vecchia Stefano , Gelsomino Fabio , Tassinari Davide , Tamberi Stefano , Bernardini Ilaria , Accettura Caterina , Frassineti Giovanni Luca , Amadori Dino , Nanni Oriana 
Published: July 2020

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired. Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported. Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68–0.95, p = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72–1.12, p = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49–0.84, p = 0.0011) versus CT alone. Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.
A learning agenda to build the evidence base for strengthening global health information systems
Authors: Reynolds Heidi W , Salentine Shannon , Silvestre Eva , Millar Elizabeth , Strahley Ashley , Cannon Abby C , Bobrow Emily A 
Published: July 2020

Background: Evidence-based interventions are necessary for planning and investing in health information systems (HIS) and for strengthening those systems to collect, manage, sort and analyse health data to support informed decision-making. However, evidence and guidance on HIS strengthening in low- and middle-income countries have been historically lacking. Objective: This article describes the approach, methods, lessons learned and recommendations from 5 years of applying our learning agenda to strengthen the evidence base for effective HIS interventions. Methods: The first step was to define key questions about characteristics, stages of progression, and factors and conditions of HIS performance progress. We established a team and larger advisory group to guide the implementation of activities to build the evidence base to answer questions. We strengthened learning networks to share information. Results: The process of applying the learning agenda provided a unique opportunity to learn by doing, strategically collecting information about monitoring and evaluating HIS strengthening interventions and building a body of evidence. There are now models and tools to strengthen HIS, improved indicators and measures, country HIS profiles, documentation of interventions, a searchable database of HIS assessment tools and evidence generated through syntheses and evaluation results. Conclusion: The systematic application of learning agenda processes and activities resulted in increased evidence, information, guidance and tools for HIS strengthening and a resource centre, making that information accessible and available globally. Implications: We describe the inputs, processes and lessons learned, so that others interested in designing a successful learning agenda have access to evidence of how to do so.
Differences in measurement of high-sensitivity troponin in an on-demand and batch-wise setting
Authors: Sörensen Nils Arne , Neumann Johannes Tobias , Ojeda Francisco , Renné Thomas , Karakas Mahir , Blankenberg Stefan , Westermann Dirk , Zeller Tanja 
Published: July 2020

Abstract

Background
Most studies assessing the diagnostic value of high-sensitivity troponin in the diagnosis of myocardial infarction used batch-wise analyses of frozen samples for high-sensitivity troponin measurements. Whether the accuracy of these batch-wise high-sensitivity troponin measurements described in diagnostic studies is comparable to clinical routine is unknown.

Methods
We enrolled 937 patients presenting with suspected myocardial infarction in this prospective cohort study. Measurements of high-sensitivity troponin I (Abbott Architect) and high-sensitivity troponin T (Roche) were performed in two settings: (a) on-demand in clinical routine using fresh blood samples; and (b) in batches using frozen blood samples from the same individuals at three timepoints (0 hours, 1 hour and 3 hours after presentation).

Results
Median troponin levels were not different between on-demand and batch-wise measurements. Troponin levels in the range of 0 to 40 ng/L showed a very high correlation between the on-demand and batch setting (Pearson correlation coefficient (r) was 0.92–0.95 for high-sensitivity troponin I and 0.96 for high-sensitivity troponin T). However, at very low troponin levels (0 to 10 ng/L) correlation between the two settings was moderate (r for high-sensitivity troponin I 0.59–0.66 and 0.65–0.69 for high-sensitivity troponin T). Application of guideline-recommended rapid diagnostic algorithms showed similar diagnostic performance with both methods.

Conclusions
Overall on-demand and batch-wise measurements of high-sensitivity troponin provided similar results, but their correlation was moderate, when focusing on very low troponin levels. The application of rapid diagnostic algorithms was safe in both settings.

Trial Registration
www.clinicaltrials.gov (NCT02355457)
Glucose-6-phosphate dehydrogenase deficiency
Authors: Luzzatto Lucio , Ally Mwashungi , Notaro Rosario 
Published: July 2020

AbstractGlucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD. G6PD deficiency makes red cells highly vulnerable to oxidative damage, and therefore susceptible to hemolysis. Over 200 G6PD mutations are known: approximately one-half are polymorphic and therefore common in various populations. Some 500 million persons with any of these mutations are mostly asymptomatic throughout their lifetime; however, any of them may develop acute and sometimes very severe hemolytic anemia when triggered by ingestion of fava beans, by any of a number of drugs (for example, primaquine, rasburicase), or, more rarely, by infection. Approximately one-half of the G6PD mutations are instead sporadic: rare patients with these mutations present with chronic nonspherocytic hemolytic anemia. Almost all G6PD mutations are missense mutations, causing amino acid replacements that entail deficiency of G6PD enzyme activity: they compromise the stability of the protein, the catalytic activity is decreased, or a combination of both mechanisms occurs. Thus, genotype-phenotype correlations have been reasonably well clarified in many cases. G6PD deficiency correlates remarkably, in its geographic distribution, with past/present malaria endemicity: indeed, it is a unique example of an X-linked human polymorphism balanced through protection of heterozygotes from malaria mortality. Acute hemolytic anemia can be managed effectively provided it is promptly diagnosed. Reliable diagnostic procedures are available, with point-of-care tests becoming increasingly important where primaquine and its recently introduced analog tafenoquine are required for the elimination of malaria.
Red cell membrane disorders: structure meets function
Authors: Risinger Mary , Kalfa Theodosia A. 
Published: July 2020

Abstract
The mature red blood cell (RBC) lacks a nucleus and organelles characteristic of most cells, but it is elegantly structured to perform the essential function of delivering oxygen and removing carbon dioxide from all other cells while enduring the shear stress imposed by navigating small vessels and sinusoids. Over the past several decades, the efforts of biochemists, cell and molecular biologists, and hematologists have provided an appreciation of the complexity of RBC membrane structure, while studies of the RBC membrane disorders have offered valuable insights into structure–function relationships. Within the last decade, advances in genetic testing and its increased availability have made it possible to substantially build upon this foundational knowledge. Although disorders of the RBC membrane due to altered structural organization or altered transport function are heterogeneous, they often present with common clinical findings of hemolytic anemia. However, they may require substantially different management depending on the underlying pathophysiology. Accurate diagnosis is essential to avoid emergence of complications or inappropriate interventions. We propose an algorithm for laboratory evaluation of patients presenting with symptoms and signs of hemolytic anemia with a focus on RBC membrane disorders. Here, we review the genotypic and phenotypic variability of the RBC membrane disorders in order to raise the index of suspicion and highlight the need for correct and timely diagnosis.
Diamond-Blackfan anemia
Authors: Da Costa Lydie , Leblanc Thierry , Mohandas Narla 
Published: July 2020

AbstractDiamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.
Congenital dyserythropoietic anemias
Authors: Iolascon Achille , Andolfo Immacolata , Russo Roberta 
Published: July 2020

AbstractCongenital dyserythropoietic anemias (CDAs) are a heterogeneous group of inherited anemias that affect the normal differentiation–proliferation pathways of the erythroid lineage. They belong to the wide group of ineffective erythropoiesis conditions that mainly result in monolinear cytopenia. CDAs are classified into the 3 major types (I, II, III), plus the transcription factor-related CDAs, and the CDA variants, on the basis of the distinctive morphological, clinical, and genetic features. Next-generation sequencing has revolutionized the field of diagnosis of and research into CDAs, with reduced time to diagnosis, and ameliorated differential diagnosis in terms of identification of new causative/modifier genes and polygenic conditions. The main improvements regarding CDAs have been in the study of iron metabolism in CDAII. The erythroblast-derived hormone erythroferrone specifically inhibits hepcidin production, and its role in the mediation of hepatic iron overload has been dissected out. We discuss here the most recent advances in this field regarding the molecular genetics and pathogenic mechanisms of CDAs, through an analysis of the clinical and molecular classifications, and the complications and clinical management of patients. We summarize also the main cellular and animal models developed to date and the possible future therapies.
The impact of scrubber discharge on the water quality in estuaries and ports
Authors: Teuchies Johannes , Cox Tom J. S. , Van Itterbeeck Katrien , Meysman Filip J. R. , Blust Ronny 
Published: July 2020

Abstract
Background
The International Maritime Organization (IMO) has set limits on sulphur content in fuels for marine transport. However, vessels continue to use these residual high-sulphur fuels in combination with exhaust gas cleaning systems (EGCS or scrubbers). Next to high sulphur, combustion of these fuels also results in higher emissions of contaminants including metals and PAHs. In scrubbers, exhaust gases are sprayed with water in order to remove SOx, resulting in acidic washwater with elevated contaminant concentrations discharged in the aquatic ecosystem. The number of vessels with scrubbers is increasing rapidly, but knowledge on washwater quality and impact are limited.

Results
The scrubber washwater is found to be acidic with elevated concentrations of, e.g. zinc, vanadium, copper, nickel, phenanthrene, naphthalene, fluorene and fluoranthene. Model calculations on the effects of scrubber discharge under scenario HIGH (20% of vessels, 90th percentile concentrations) on the water quality in harbour docks showed a decrease in pH of 0.015 units and an increase in surface water concentrations for e.g. naphthalene (189% increase) and vanadium (46% increase).

Conclusions
The IMO established sulphur regulations to mitigate the impact of high sulphur emissions of the maritime sector. However, the use of open-loop scrubbers as an abatement technology will not reduce their contribution to ocean acidification. In addition, different types of scrubbers discharge washwater that is acutely toxic for aquatic organisms. However, washwater is diluted and the compounds for which a large increase in surface water concentrations was calculated in the Antwerp (Belgium) harbour docks (naphthalene > phenanthrene > fluorene > acenaphthene > vanadium) were not the compounds that already exceed their respective Water Quality Standards (WQS). Nevertheless, the WQS of several ‘priority hazardous substances’ (Water Framework Directive) are already exceeded in the docks and the Scheldt estuary. Since these hazardous substances are also identified in the washwater, scrubber washwater discharge should be discouraged in coastal waters and estuaries with large ecological value.
BiPOm: a rule-based ontology to represent and infer molecule knowledge from a biological process-centered viewpoint
Authors: Henry Vincent , Saïs Fatiha , Inizan Olivier , Marchadier Elodie , Dibie Juliette , Goelzer Anne , Fromion Vincent 
Published: July 2020

Abstract
Background
Managing and organizing biological knowledge remains a major challenge, due to the complexity of living systems. Recently, systemic representations have been promising in tackling such a challenge at the whole-cell scale. In such representations, the cell is considered as a system composed of interlocked subsystems. The need is now to define a relevant formalization of the systemic description of cellular processes.

Results
We introduce BiPOm (Biological interlocked Process Ontology for metabolism) an ontology to represent metabolic processes as interlocked subsystems using a limited number of classes and properties. We explicitly formalized the relations between the enzyme, its activity, the substrates and the products of the reaction, as well as the active state of all involved molecules. We further showed that the information of molecules such as molecular types or molecular properties can be deduced by automatic reasoning using logical rules. The information necessary to populate BiPOm can be extracted from existing databases or existing bio-ontologies.

Conclusion
BiPOm provides a formal rule-based knowledge representation to relate all cellular components together by considering the cellular system as a whole. It relies on a paradigm shift where the anchorage of knowledge is rerouted from the molecule to the biological process.

Availability
BiPOm can be downloaded at https://github.com/SysBioInra/SysOnto
Drug-target interactions prediction using marginalized denoising model on heterogeneous networks
Authors: Tang Chunyan , Zhong Cheng , Chen Danyang , Wang Jianyi 
Published: July 2020

Abstract
Background
Drugs achieve pharmacological functions by acting on target proteins. Identifying interactions between drugs and target proteins is an essential task in old drug repositioning and new drug discovery. To recommend new drug candidates and reposition existing drugs, computational approaches are commonly adopted. Compared with the wet-lab experiments, the computational approaches have lower cost for drug discovery and provides effective guidance in the subsequent experimental verification. How to integrate different types of biological data and handle the sparsity of drug-target interaction data are still great challenges.

Results
In this paper, we propose a novel drug-target interactions (DTIs) prediction method incorporating marginalized denoising model on heterogeneous networks with association index kernel matrix and latent global association. The experimental results on benchmark datasets and new compiled datasets indicate that compared to other existing methods, our method achieves higher scores of AUC (area under curve of receiver operating characteristic) and larger values of AUPR (area under precision-recall curve).

Conclusions
The performance improvement in our method depends on the association index kernel matrix and the latent global association. The association index kernel matrix calculates the sharing relationship between drugs and targets. The latent global associations address the false positive issue caused by network link sparsity. Our method can provide a useful approach to recommend new drug candidates and reposition existing drugs.
Males of a sexually cannibalistic spider chemically assess relative female quality
Authors: Cory Anna-Lena , Schneider Jutta M. 
Published: July 2020

Abstract
Background
Mate choice is a taxonomically wide-spread phenomenon, mostly exerted by females although male mate choice occurs as well. While costs and benefits of choosiness have been well studied, the underlying mechanisms are largely unclear. Different models exist, namely best-of-n or threshold rules, based on sequential or simultaneous sampling, which differ in the required cognitive demands. We applied an experimental approach to shed light on the underlying mechanisms of male mate choice in the sexually cannibalistic spider Argiope bruennichi. Males are limited to two copulations and preferentially monopolise large females, while they may leave smaller females after a single copulation and resume mate search. Here, we utilised significant size-differences between females from Northern and Southern populations and presented males with three different-sized females that were matched for origin: all three females originated either from the same Northern European population as the males or from Southern populations where the smallest female was about the same size as the largest Northern female. This allowed testing the hypothesis that males base their mating tactic on a fixed local size threshold. We predicted Northern males to be choosy among Northern females, but to accept all Southern females since they would all be above that threshold.

Results
Males copulated with the first female they encountered, which was independent of her body size. Regardless of the females’ origins, males chose a monogynous tactic with the largest female in the trio, while they left the smallest female after one copulation. The same pattern applied to Southern females even though the smallest females in the trio were of a similar size as monopolised Northern females. Since males have poor eyesight and did not actively sample all females, they likely have gained information about relative size differences between females based on volatile chemical cues only.

Conclusions
Our findings suggest that male A. bruennichi can assess relative differences in mate quality and adjust their mating tactic to the prevailing conditions (Northern vs. Southern). We reject the presence of a locally-adapted fixed threshold and argue that our results are best explained by an adjustable threshold that was raised under Southern conditions.
Identification of candidate genes and regulatory factors related to growth rate through hypothalamus transcriptome analyses in broiler chickens
Authors: Piórkowska Katarzyna , Żukowski Kacper , Połtowicz Katarzyna , Nowak Joanna , Ropka-Molik Katarzyna , Derebecka Natalia , Wesoły Joanna , Wojtysiak Dorota 
Published: July 2020

Abstract
Background
Intensive selection for growth rate (GR) in broiler chickens carries negative after-effects, such as aberrations in skeletal development and the immune system, heart failure, and deterioration of meat quality. In Poland, fast-growing chicken populations are highly non-uniform in term of growth rate, which is highly unprofitable for poultry producers. Therefore, the identification of genetic markers for boiler GR that could support the selection process is needed. The hypothalamus is strongly associated with growth regulation by inducing important pituitary hormones. Therefore, the present study used this tissue to pinpoint genes involved in chicken growth control.

Results
The experiment included male broilers of Ross 308 strain in two developmental stages, after 3rd and 6th week of age, which were maintained in the same housing and feeding conditions. The obtained results show for the overexpression of genes related to orexigenic molecules, such as neuropeptide Y (NPY), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), galanin (GAL), and pro-melanin concentrating hormone (PMCH) in low GR cockerels.

Conclusion
The results reveal strong associations between satiety centre and the growth process. The present study delivers new insights into hypothalamic regulation in broiler chickens and narrows the area for the searching of genetic markers for GR.

Graphical abstract