Biosimilar: what it is not Mora, Fernando
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
November 2015, Letnik:
80, Številka:
5
Journal Article
Recenzirano
Odprti dostop
A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a ...safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence‐based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not…and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a ‘stand‐alone’. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA's criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so‐called non‐original biologics (NOB), i.e. non‐biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients
Abstract Current methodologies of genome‐wide single‐nucleotide polymorphism (SNP) genotyping produce large amounts of missing data that may affect statistical inference and bias the outcome of ...experiments. Genotype imputation is routinely used in well‐studied species to buffer the impact in downstream analysis, and several algorithms are available to fill in missing genotypes. The lack of reference haplotype panels precludes the use of these methods in genomic studies on non‐model organisms. As an alternative, machine learning algorithms are employed to explore the genotype data and to estimate the missing genotypes. Here, we propose an imputation method based on self‐organizing maps (SOM), a widely used neural networks formed by spatially distributed neurons that cluster similar inputs into close neurons. The method explores genotype datasets to select SNP loci to build binary vectors from the genotypes, and initializes and trains neural networks for each query missing SNP genotype. The SOM‐derived clustering is then used to impute the best genotype. To automate the imputation process, we have implemented gtImputation , an open‐source application programmed in Python3 and with a user‐friendly GUI to facilitate the whole process. The method performance was validated by comparing its accuracy, precision and sensitivity on several benchmark genotype datasets with other available imputation algorithms. Our approach produced highly accurate and precise genotype imputations even for SNPs with alleles at low frequency and outperformed other algorithms, especially for datasets from mixed populations with unrelated individuals.
The increase of sequencing capacity provided by high‐throughput platforms has made it possible to routinely obtain large sets of genomic and transcriptomic sequences from model and non‐model ...organisms. Subsequent genomic analysis and gene discovery in next‐generation sequencing experiments are, however, bottlenecked by functional annotation. One common way to perform functional annotation of sets of sequences obtained from next‐generation sequencing experiments, is by searching for homologous sequences and accessing the related functional information deposited in genomic databases. Functional annotation is especially challenging for non‐model organisms, like many plant species. In such cases, existing free and commercial general‐purpose applications may not offer complete and accurate results. We present TOA (Taxonomy‐oriented annotation), a Python‐based user‐friendly open source application designed to establish functional annotation pipelines geared towards non‐model plant species that can run in Linux/Mac computers, HPCs and cloud servers. TOA performs homology searches against proteins stored in the PLAZA databases, NCBI RefSeq Plant, Nucleotide Database and Non‐Redundant Protein Sequence Database, and outputs functional information from several ontology systems: Gene Ontology, InterPro, EC, KEGG, Mapman and MetaCyc. The software performance was validated by comparing the runtimes, total number of annotated sequences and accuracy of the functional information obtained for several plant benchmark data sets with TOA and other functional annotation solutions. TOA outperformed the other software in terms of number of annotated sequences and accuracy of the annotation and constitutes a good alternative to improve functional annotation in plants. TOA is especially recommended for gymnosperms or for low quality sequence data sets of non‐model plants.
•Clinical studies showed that PGE2 may exert a protective effect in asthmatics.•EP receptors and available agonists are of therapeutic interest.•PGE2 attenuates mast cell activity in vitro and in ...vivo through EP2 agonism.•EP2-mediated mast cell restraining explains the PGE2-driven reduced airway damage.•Understanding the PGE2–EP2–mast cell axis may uncover antiasthma targets.
Despite the fact that cyclooxygenase and its products, prostaglandins, have been traditionally associated with the development of inflammation, PGE2 was implicated early on as potentially beneficial in asthma. During the 1970s and 1980s, several studies reported the bronchodilator effect of PGE2 in asthma patients. In parallel, it was being shown to exert an inhibitory effect on mast cells in vitro. In spite of this, data supporting the beneficial role for PGE2 in asthma were scarce and sometimes controversial.
Many years later, in vitro and in vivo studies suggested a range of biological activities attributable to PGE2, others than the ability to relax smooth muscle, that potentially explained some of the observed positive effects in asthma. The identification and cloning of the four PGE2 receptors made available new tools with which to fine-tune investigation of the anti-inflammatory, pro-inflammatory, immunoregulatory, and bronchodilation mechanisms of PGE2. Among these, several suggested involvement of mast cells, a cell population known to play a fundamental role in acute and chronic asthma. Indeed, it has been shown that PGE2 prevents human and murine MC activity in vitro through activation of the EP2 receptor, and also that both exogenously administered and endogenous PGE2 inhibit airway MC activity in vivo in mouse models of asthma (likely through an EP2-mediated mechanism as well). In the last few years, we have furthered into the functional connection between PGE2-induced mast cells inhibition and attenuated damage, in asthma and allergy models. The validity of the findings supporting a beneficial effect of PGE2 in different asthma phases, the direct effect of PGE2 on mast cells populations, and the functional implications of the PGE2–MC interaction on airway function are some of the topics addressed in this review, under the assumption that increased understanding of the PGE2–EP2–mast cell axis will likely lead to the discovery of novel antiasthma targets.
A topoclimate model for Quaternary insular speciation García‐Olivares, Víctor; Patiño, Jairo; Overcast, Isaac ...
Journal of biogeography,
December 2019, 2019-12-00, 20191201, Letnik:
46, Številka:
12
Journal Article
Recenzirano
Aim
Understanding the drivers of speciation within islands is key to explain the high levels of invertebrate diversification and endemism often observed within islands. Here, we propose an insular ...topoclimate model for Quaternary diversification (ITQD), and test the general prediction that, within a radially eroded conical island, glacial climate conditions facilitate the divergence of populations within species across valleys.
Location
Gran Canaria, Canary Islands.
Taxon
The Laparocerus tessellatus beetle species complex (Coleoptera, Curculionidae).
Methods
We characterize individual‐level genomic relationships using single nucleotide polymorphisms produced by double‐digest restriction site associated DNA sequencing (ddRAD‐seq). A range of parameter values were explored in order to filter our data. We assess individual relatedness, species boundaries, demographic history and spatial patterns of connectivity.
Results
The total number of ddRAD‐seq loci per sample ranges from 4,576 to 512, with 11.12% and 4.84% of missing data respectively, depending on the filtering parameter combination. We consistently infer four genetically distinct ancestral populations and two presumed cases of admixture, one of which is largely restricted to high altitudes. Bayes factor delimitation support the hypothesis of four species, which is consistent with the four inferred ancestral gene pools. Landscape resistance analyses identified genomic relatedness among individuals in two out of the four inferred species to be best explained by annual precipitation during the last glacial maximum rather than geographic distance.
Main conclusions
Our data reveal a complex speciation history involving population isolation and admixture, with broad support for the ITQD model here proposed. We suggest that further studies are needed to test the generality of our model, and enrich our understanding of the evolutionary process in island invertebrates. Our results demonstrate the power of ddRAD‐seq data to provide a detailed understanding of the temporal and spatial dynamics of insular biodiversity.
Engagement of EP2 receptors dampens mast cell IgE‐dependent signaling causing suppression of FcɛRI‐mediated allergic responses; thus agonism of EP2 may be beneficial in allergic diseases.
The ...experimental administration of PGE2 for the treatment of asthma dampens clinical symptoms, and similar efficacy has been found in dust mite‐induced hypersensitivity reactions in animal models. Here, we investigate the mechanism by which PGE2 mediates suppression of MC degranulation. We find that the effect of PGE2 on FcɛRI‐dependent MC degranulation varies from activating to suppressing, depending on the relative ratio of EP2 to EP3 expression on these cells with suppression evident only in cells having increased EP2 to EP3 expression. Consistent with a role for EP2 in suppressing MC responses in vitro, we found that a selective EP2 agonist, Butaprost, inhibited MC‐mediated FcɛRI‐induced immediate hypersensitivity in a model of PCA. EP2 engagement on MCs increased cAMP production and inhibited FcɛRI‐mediated calcium influx. In addition, it also decreased the extent of FcɛRI‐induced Fyn kinase activity, leading to decreased phosphorylation of key signaling molecules such as Gab2 and Akt. Treatment with an antagonist of cAMP or shRNA down‐regulation of PKA (the principal intracellular target of cAMP) reversed the EP2‐mediated inhibitory effect on MC degranulation and restored calcium influx and phosphorylation of Akt. Collectively, the findings demonstrate that EP2 suppresses the Fyn‐mediated signals that are central to FcɛRI‐dependent MC degranulation, suggesting that engagement of the EP2 on MCs may be beneficial in dampening allergic responses.
Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased ...airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB.
This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction.
We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP(1-4) were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed.
Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP(2) and EP(4) receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone.
Our data show a protective role for the PGE2 receptors EP(2) and EP(4) following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Which library should I use? de la Mora, Fernando López; Nadi, Sarah
2018 IEEE/ACM 40th International Conference on Software Engineering: New Ideas and Emerging Technologies Results (ICSE-NIER),
05/2018
Conference Proceeding
Software libraries ease development tasks by allowing client developers to reuse code written by third parties. To perform a specific task, there is usually a large number of libraries that offer the ...desired functionality. Unfortunately, selecting the appropriate library to use is not straightforward since developers are often unaware of the advantages and disadvantages of each library, and may also care about different characteristics in different situations. In this paper, we introduce the idea of using software metrics to help developers choose the libraries most suited to their needs. We propose creating library comparisons based on several metrics extracted from multiple sources such as software repositories, issue tracking systems, and Q&A websites. By consolidating all of this information in a single website, we enable developers to make informed decisions by comparing metric data belonging to libraries from several domains. Additionally, we will use this website to survey developers about which metrics are the most valuable to them, helping us answer the broader question of what determines library quality. In this short paper, we describe the metrics we propose in our work and present preliminary results, as well as faced challenges.
Biosimilar and interchangeable: Inseparable scientific concepts? Mora, Fernando; Balsa, Alejandro; Cornide‐Santos, María ...
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
November 2019, Letnik:
85, Številka:
11
Journal Article
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