IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-06-23 DOI: 10.14573/altex.1401283

Catherine Willett, Jessica Caverly Rae, Katy O Goyak, Brigitte Landesmann, Gary Minsavage, Carl Westmoreland

引用次数: 20

A k-NN algorithm for predicting the oral sub-chronic toxicity in the rat. 预测大鼠口腔亚慢性毒性的k-NN算法。

IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-07-10 DOI: 10.14573/altex.1405091

Domenico Gadaleta, Fabiola Pizzo, Anna Lombardo, Angelo Carotti, Sylvia E Escher, Orazio Nicolotti, Emilio Benfenati

{"title":"A k-NN algorithm for predicting the oral sub-chronic toxicity in the rat.","authors":"Domenico Gadaleta, Fabiola Pizzo, Anna Lombardo, Angelo Carotti, Sylvia E Escher, Orazio Nicolotti, Emilio Benfenati","doi":"10.14573/altex.1405091","DOIUrl":"https://doi.org/10.14573/altex.1405091","url":null,"abstract":"Repeated dose toxicity is of the utmost importance to characterize the toxicological profile of a chemical after repeated administration. Its evaluation refers to the Lowest-Observed-(Adverse)-Effect-Level (LO(A)EL) explicitly requested in several regulatory contexts, such as REACH and EC Regulation 1223/2009 on cosmetic products. So far in vivo tests have been the sole viable option to assess repeated dose toxicity. We report a customized k-Nearest Neighbors approach for predicting sub-chronic oral toxicity in rats. A training set of 254 chemicals was used to derive models whose robustness was challenged through leave-one-out cross-validation. Their predictive power was evaluated on an external dataset comprising 179 chemicals. Despite the intrinsically heterogeneous nature of the data, our models give promising results, with q²≥0.632 and external r²≥0.543. The confidence in prediction was ensured by implementing restrictive user-adjustable rules excluding suspicious chemicals irrespective of the goodness in their prediction. Comparison with the very few LO(A)EL predictive models in the literature indicates that the results of the present analysis can be valuable in prioritizing the safety assessment of chemicals and thus making safe decisions and justifying waiving animal tests according to current regulations concerning chemical safety.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"423-32"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32522266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 18

30th anniversary of ALTEX. ALTEX成立30周年。

IF 5.6

ALTEX Pub Date : 2014-01-01

Sonja von Aulock

引用次数: 0

Alternative methods for the use of non-human primates in biomedical research. 在生物医学研究中使用非人类灵长类动物的替代方法。

IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-07-24 DOI: 10.14573/altex.1406231

Saskia M Burm, Jan-Bas Prins, Jan Langermans, Jeffrey J Bajramovic

{"title":"Alternative methods for the use of non-human primates in biomedical research.","authors":"Saskia M Burm, Jan-Bas Prins, Jan Langermans, Jeffrey J Bajramovic","doi":"10.14573/altex.1406231","DOIUrl":"https://doi.org/10.14573/altex.1406231","url":null,"abstract":"The experimental use of non-human primates (NHP) in Europe is tightly regulated and is only permitted when there are no alternatives available. As a result, NHP are most often used in late, pre-clinical phases of biomedical research. Although the impetus for scientists, politicians and the general public to replace, reduce and refine NHP in biomedical research is strong, the development of 3Rs technology for NHP poses specific challenges. In February 2014 a workshop on \"Alternative methods for the use of NHP in biomedical research\" was organized within the international exchange program of EUPRIM-Net II, a European infrastructure initiative that links biomedical primate research centers. The workshop included lectures by key scientists in the field of alternatives as well as by experts from governmental and non-governmental organizations. Furthermore, parallel sessions were organized to stimulate discussion on the challenges of advancing the use of alternative methods for NHP. Subgroups voted on four statements and together composed a list with opportunities and priorities. This report summarizes the presentations that were held, the content of the discussion sessions and concludes with recommendations on 3Rs development for NHP specifically. These include technical, conceptual as well as political topics.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"520-9"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32531405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Spinal cord--skeletal muscle cocultures detect muscle-relaxant action of botulinum neurotoxin A. 脊髓-骨骼肌共培养检测肉毒杆菌神经毒素A的肌肉松弛作用。

IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-08-14 DOI: 10.14573/altex.1304291

Veit-Simon Eckle, Berthold Drexler, Christian Grasshoff, Thomas Seeger, Horst Thiermann, Bernd Antkowiak

{"title":"Spinal cord--skeletal muscle cocultures detect muscle-relaxant action of botulinum neurotoxin A.","authors":"Veit-Simon Eckle, Berthold Drexler, Christian Grasshoff, Thomas Seeger, Horst Thiermann, Bernd Antkowiak","doi":"10.14573/altex.1304291","DOIUrl":"https://doi.org/10.14573/altex.1304291","url":null,"abstract":"The mouse LD50 assay is routinely used for potency testing of botulinum toxins. Unfortunately, this test is associated with severe pain and distress in animals and requires large quantities of mice. Here we used cocultures of spinal cord and muscle tissue as an alternative for probing botulinum toxins. Cocultures were prepared from mouse embryonic tissue (C57/BL6J) and cultured for 24-27 days. In these cultures spontaneous muscle activity was quantified in sham- and botulinum toxin-treated cultures for up to 3 days by video microscopy. At a concentration of 58 fmol/L or higher, incobotulinumtoxin A significantly reduced the frequency of muscle contractions within 24 hours after incubation. Hence, nerve-muscle-cultures are similar sensitive as the mouse LD50 assay. The limit of detection, as observed in our study, is close to the most sensitive cell-based bioassays, capable to detect concentrations of botulinum neurotoxin A between 30 and 50 fmol/L. However, spontaneous muscle activity of individual cultures displayed considerable fluctuations when evaluated on a day-to-day basis. Generally, the authors would like to emphasize, that in its present form, this in vitro assay might be too laborious for botulinum toxin potency testing. Thus, methodical improvements to decrease data variability are the next milestone to be passed towards developing this model into an assay that can be utilized for reducing animal experimentation.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"433-40"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32588944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Number of animals used for experimental purposes lower in the European Union. 在欧盟，用于实验目的的动物数量较少。

IF 5.6

ALTEX Pub Date : 2014-01-01

Sonja von Aulock

引用次数: 0

Current approaches and future role of high content imaging in safety sciences and drug discovery. 目前的方法和未来的作用，在安全科学和药物发现的高含量成像。

IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-07-14 DOI: 10.14573/altex.1405271

Erwin van Vliet, Mardas Daneshian, Mario Beilmann, Anthony Davies, Eugenio Fava, Roland Fleck, Yvon Julé, Manfred Kansy, Stefan Kustermann, Peter Macko, William R Mundy, Adrian Roth, Imran Shah, Marianne Uteng, Bob van de Water, Thomas Hartung, Marcel Leist

{"title":"Current approaches and future role of high content imaging in safety sciences and drug discovery.","authors":"Erwin van Vliet, Mardas Daneshian, Mario Beilmann, Anthony Davies, Eugenio Fava, Roland Fleck, Yvon Julé, Manfred Kansy, Stefan Kustermann, Peter Macko, William R Mundy, Adrian Roth, Imran Shah, Marianne Uteng, Bob van de Water, Thomas Hartung, Marcel Leist","doi":"10.14573/altex.1405271","DOIUrl":"https://doi.org/10.14573/altex.1405271","url":null,"abstract":"High content imaging combines automated microscopy with image analysis approaches to simultaneously quantify multiple phenotypic and/or functional parameters in biological systems. The technology has become an important tool in the fields of safety sciences and drug discovery, because it can be used for mode-of-action identification, determination of hazard potency and the discovery of toxicity targets and biomarkers. In contrast to conventional biochemical endpoints, high content imaging provides insight into the spatial distribution and dynamics of responses in biological systems. This allows the identification of signaling pathways underlying cell defense, adaptation, toxicity and death. Therefore, high content imaging is considered a promising technology to address the challenges for the \"Toxicity testing in the 21st century\" approach. Currently, high content imaging technologies are frequently applied in academia for mechanistic toxicity studies and in pharmaceutical industry for the ranking and selection of lead drug compounds or to identify/confirm mechanisms underlying effects observed in vivo. A recent workshop gathered scientists working on high content imaging in academia, pharmaceutical industry and regulatory bodies with the objective to compile the state-of-the-art of the technology in the different institutions. Together they defined technical and methodological gaps, proposed quality control measures and performance standards, highlighted cell sources and new readouts and discussed future requirements for regulatory implementation. This review summarizes the discussion, proposed solutions and recommendations of the specialists contributing to the workshop.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"479-93"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32506277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 41

A human dendritic cell-based in vitro model to assess Mycobacterium tuberculosis SO2 vaccine immunogenicity. 基于人树突状细胞的体外模型评估结核分枝杆菌SO2疫苗的免疫原性。

IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-05-20 DOI: 10.14573/altex.1311041

Marilena P Etna, Elena Giacomini, Martina Severa, Manuela Pardini, Nacho Aguilo, Carlos Martin, Eliana M Coccia

{"title":"A human dendritic cell-based in vitro model to assess Mycobacterium tuberculosis SO2 vaccine immunogenicity.","authors":"Marilena P Etna, Elena Giacomini, Martina Severa, Manuela Pardini, Nacho Aguilo, Carlos Martin, Eliana M Coccia","doi":"10.14573/altex.1311041","DOIUrl":"https://doi.org/10.14573/altex.1311041","url":null,"abstract":"Among the tuberculosis (TB) vaccine candidates, SO2 is the prototype of the first live-attenuated vaccine that recently entered into clinical trials. To investigate the capacity of SO2 to stimulate an appropriate immune response in vitro within a human immunological context, a comparative analysis of the effects promoted by SO2, the current Bacille Calmette-Guerin (BCG) vaccine and Mycobacterium tuberculosis (Mtb) was conducted in human primary dendritic cells (DC), which are critical modulators of vaccine-induced immunity. In particular, we found that SO2 promotes the expression of maturation markers similarly to BCG but at a lower extent than Mtb. Moreover, SO2-infected DC released higher levels of interleukin (IL)-23 than BCG-infected cells, which account for the expansion of interferon (IFN)-γ-producing T cells in an IL-12-independent manner. In the autologous mixed leukocyte reaction setting, the expansion of IL-17-producing T cells was also observed in response to SO2 infection. Interestingly, apoptosis and autophagic flux, events required for the antigen presentation within MHC class II complex, were not affected in DC infected with SO2, conversely to what observed upon Mtb stimulation. Collectively, our results indicate that SO2 represents a promising TB vaccine candidate, which displays an attenuated phenotype and promotes in DC a stronger capacity to stimulate the Th response than BCG vaccine. Interestingly, the data obtained by using the human DC-based experimental setting mirrored the results derived from studies in animal models, suggesting that this system could be used for an efficient and rapid down-selection of new TB vaccine candidates, contributing to achieve the \"3Rs\" objective.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"397-406"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32351628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 18

Building shared experience to advance practical application of pathway-based toxicology: liver toxicity mode-of-action. 建立共享经验以推进基于途径的毒理学的实际应用:肝毒性作用模式。

IF 5.6

ALTEX Pub Date : 2014-01-01 Epub Date: 2014-01-28 DOI: 10.14573/altex.1401281

Catherine Willett, Jessica Caverly Rae, Katy O Goyak, Gary Minsavage, Carl Westmoreland, Melvin Andersen, Mark Avigan, Daniel Duché, Georgina Harris, Thomas Hartung, Hartmut Jaeschke, Andre Kleensang, Brigitte Landesmann, Suzanne Martos, Marilyn Matevia, Colleen Toole, Andrew Rowan, Terry Schultz, Jennifer Seed, John Senior, Imran Shah, Kalyanasundaram Subramanian, Mathieu Vinken, Paul Watkins

{"title":"Building shared experience to advance practical application of pathway-based toxicology: liver toxicity mode-of-action.","authors":"Catherine Willett, Jessica Caverly Rae, Katy O Goyak, Gary Minsavage, Carl Westmoreland, Melvin Andersen, Mark Avigan, Daniel Duché, Georgina Harris, Thomas Hartung, Hartmut Jaeschke, Andre Kleensang, Brigitte Landesmann, Suzanne Martos, Marilyn Matevia, Colleen Toole, Andrew Rowan, Terry Schultz, Jennifer Seed, John Senior, Imran Shah, Kalyanasundaram Subramanian, Mathieu Vinken, Paul Watkins","doi":"10.14573/altex.1401281","DOIUrl":"https://doi.org/10.14573/altex.1401281","url":null,"abstract":"A workshop sponsored by the Human Toxicology Project Consortium (HTPC), \"Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action\" brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is extremely helpful. In addition, it is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"500-19"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779550/pdf/nihms-763117.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32122530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 16

Experiences of the REACH testing proposals system to reduce animal testing. 减少动物试验的REACH测试提案系统的经验。

IF 5.6

ALTEX Pub Date : 2014-01-01 DOI: 10.14573/altex.1311151

Katy Taylor, Wolfgang Stengel, Carlotta Casalegno, David Andrew

{"title":"Experiences of the REACH testing proposals system to reduce animal testing.","authors":"Katy Taylor, Wolfgang Stengel, Carlotta Casalegno, David Andrew","doi":"10.14573/altex.1311151","DOIUrl":"https://doi.org/10.14573/altex.1311151","url":null,"abstract":"In order to reduce animal testing, companies registering chemical substances under the EU REACH legislation must propose rather than conduct certain tests on animals. Third parties can submit 'scientifically valid information' relevant to these proposals to the Agency responsible, the European Chemicals Agency (ECHA), who are obliged to take the information into account. The European Coalition to End Animal Experiments (ECEAE) provided comments on nearly half of the 817 proposals for vertebrate tests on 480 substances published for comment for the first REACH deadline (between 1 August 2009 and 31 July 2012). The paper summarises the response by registrants and the Agency to third party comments and highlights issues with the use of read across, in vitro tests, QSAR and weight of evidence approaches. Use of existing data and evidence that testing is legally or scientifically unjustified remain the most successful comments for third parties to submit. There is a worrying conservatism within the Agency regarding the acceptance of alternative approaches and examples of where registrants have also failed to maximise opportunities to avoid testing.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"107-28"},"PeriodicalIF":5.6,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40294981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

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