A few weeks ago, we received a press release that gave us pause: The University of Liverpool said it had found one of its researchers guilty of research misconduct — but did not say who, nor which papers might be involved.
Now, less than one month later, the university is naming the researcher, and identifying a paper that it has asked the journal to retract.
After we covered the opaque release, we received some tips that the scientist might be Daniel Antoine, who studies liver damage. Last week, Liverpool confirmed that Antoine is the researcher in question.
After he left Liverpool, Antoine took a position at the University of Edinburgh. However, the faculty page is now blank, and a spokesperson told Retraction Watch he is “no longer employed by the University”:
We cannot comment on the circumstances surrounding an individual member of staff leaving our employment.
The new release from Liverpool recommends retracting a 2012 paper in the Journal of Hepatology, “Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity.” The paper has been cited 170 times, according to Clarivate Analytics’ Web of Science.
We’ve reached out to Antoine at his Liverpool and Edinburgh email addresses, but haven’t heard back.
Why the sudden burst of transparency?
Just weeks ago, the University of Liverpool was declining to provide details about the case. According to a spokesperson:
We are now recommending the retraction of a specific paper and, as such, we issued an updated release with the name of that paper and the researcher involved.
However, the new release states that the investigation wrapped up months ago:
Following a detailed investigation, the panel produced its final report in March 2018, which concluded that Dr Dan Antoine, who left the University of his own volition last year, was involved in research misconduct. It found that malpractice had directly influenced and undermined the findings of the research.
Another paper in the journal co-authored by Antoine has been temporarily removed; according to the statement from Liverpool,
…a paper which is available in pre-print has been temporarily removed as a precautionary measure while its source data is verified.
The Liverpool statement says the university has launched a comprehensive review of his work. A statement from Louise Kenny, Pro-Vice-Chancellor for Health and Life Sciences, notes:
Any potential impact on patient safety is our primary concern. However we are confident, in relation to the research activity investigated thus far, that patient safety has not been compromised…I would also like to emphasise that no current and no other former employees or collaborators have been implicated as a result of the investigation.
According to a biographical statement for Antoine, he has received several young investigator awards, and his research has been funded by the European Commission, Medical Research Council, Wellcome Trust, The Royal Society and the pharmaceutical industry.
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There are ten co-authors in the retraced paper, what were the roles and contributions of the other nine researchers/co-authors in the misconduct? Are all of them innocent of misconduct? They are from three different UK and USA universities.
This RW report and that of the U of Liverpool say nothing about other co-authors and two other universities involved.
From the release: “I would also like to emphasise that no current and no other former employees or collaborators have been implicated as a result of the investigation.”
From our post, a quote attributed to Louise Kenny:
Any potential impact on patient safety is our primary concern. However we are confident, in relation to the research activity investigated thus far, that patient safety has not been compromised…I would also like to emphasise that no current and no other former employees or collaborators have been implicated as a result of the investigation.
How is it a reversal of course when anyone could have anticipated the name of the researcher would be released eventually? Just because you’re impatient for information, doesn’t necessarily mean the university didn’t have a valid reason to not release all the specifics exactly when you thought they should. There could have been legal issues that have to be ironed out, and the libel laws in the UK are ridiculous. I think you’re being unfair to the university here; you’re not entitled to all the information you want exactly when you want it.
Thanks for the feedback. From our last post, which is linked here:
Now, we might give the school a pass if it simply said it had an ongoing investigation about which it couldn’t comment. But the University of Liverpool opted to go public with the case — in the least satisfying of ways.
The statement is a masterstroke of barely relevant information masquerading as key detail, while ignoring the most important items: namely, the name itself. Knowing that an anonymized researcher possibly working hepatology — but possibly not — is of zero use to anyone else in that field or any other area.
Make the thief give back all the taxpayer money
It’s striking how often the fraudsters are winning young investigator awards and the like. Perhaps we are expecting so much of our young investigators that only fraudsters find it easy to live up to expectations.
2019 retraction.
https://www.jci.org/articles/view/129285
Original citation: J Clin Invest. 2017;127(6):2118–2132. https://doi.org/10.1172/JCI92001
Citation for this retraction: J Clin Invest. 2019;129(5):2166. https://doi.org/10.1172/JCI129285
Following an inquiry at the University of Liverpool, the Editorial Board was recently informed that the mass spectrometry data provided by Daniel J. Antoine is unreliable and likely to be fraudulent. Specifically, data relating to HMGB1 isoforms presented in Figures 1B, 2, 4A, and 5A and Supplemental Figure 3 are not reliable. Due to this finding, the JCI is retracting this article. No issues have been raised with regard to any of the other data in the paper. The corresponding author has stated that data presented in Figure 1A and data related to total HMGB1 blood levels measured by ELISA, which include that in Figure 1B, Figure 2, and Figure 4A as well as data reported in Figure 3 and Figure 4B, are reliable. The corresponding author has also stated that all supplemental figures, except those depicting HMGB1 isoforms, are reliable.
2020 expression of concern.
https://molmed.biomedcentral.com/articles/10.1186/s10020-020-0140-z
The Editors-in-Chief would like to alert readers that this article [1] is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.
Expression of Concern to: Mol Med (2010) 16:479-490
https://doi.org/10.2119/molmed.2010.00126
The Editors-in-Chief would like to alert readers that this article (Antoine et al., 2010) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1. Appropriate editorial action will be taken once the investigation is concluded.
Dominic P. Williams, Anja Kipar, and Hugh Laverty agree to this editorial expression of concern.
B. Kevin Park and Daniel J. Antoine have not responded to any correspondence from the editor/publisher about this editorial expression of concern.
Reference
Antoine DJ, et al. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatoxicity. Mol Med. 2010;16:479–90. https://doi.org/10.2119/molmed.2010.00126
2020 expression of concern.
https://molmed.biomedcentral.com/articles/10.1186/s10020-020-0142-xExpression of concern to: High systematic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome
Karin Palmblad, Hanna Schierbeck, Erik Sundberg, Anna-Carin Horne, Helena Erlandsson Harris, Jan-Inge Henter, Daniel J. Antoine & Ulf Andersson
Molecular Medicine volume 26, Article number: 17 (2020) Cite this article
11 Accesses
The Research Article to this article has been published in Molecular Medicine 2014 20:2001538
Expression of Concern to: Mol Med (2014) 20:538–547.
https://doi.org/10.2119/molmed.2014.00183
The Editors-in-Chief would like to alert readers that this article (Palmblad et al., 2014) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1. Appropriate editorial action will be taken once the investigation is concluded.
Karin Palmblad, Anna-Carin Horne, Helena Erlandsson Harris, Jan-Inge Henter, and Ulf Andersson agree to this editorial expression of concern.
Hanna Schierbeck, Erik Sundberg, and Daniel J. Antoine have not responded to any correspondence from the editor/publisher about this editorial expression of concern.
Reference
Palmblad K, et al. High systematic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome. Mol Med. 2014;20:538–47 https://molmed.biomedcentral.com/articles/10.2119/molmed.2014.00183.
2020 expression of concern.
https://molmed.biomedcentral.com/articles/10.1186/s10020-020-0143-9
Expression of Concern to: The α7 nicotine acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function
Ravikumar A. Sitapara, Daniel J. Antoine, Lokesh Sharma, Vivek S. Patel, Charles R. Ashby Jr, Samir Gorasiya, Huan Yang, Michelle Zur & Lin L. Mantell
Molecular Medicine volume 26, Article number: 16 (2020) Cite this article
16 Accesses
The Research Article to this article has been published in Molecular Medicine 2014 20:2001238
The Editors-in-Chief would like to alert readers that this article (Sitapara et al. 2014) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.
Expression of Concern to: Mol Med
https://doi.org/10.2119/molmed.2013.00086
The Editors-in-Chief would like to alert readers that this article (Sitapara et al. 2014) is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1. Appropriate editorial action will be taken once the investigation is concluded.
Lokesh Sharma, Charles R. Ashby Jr., Saamir Gorasiya, Huan Yang, and Lin L. Mantell agree to this editorial expression of concern.
Ravikumar A. Sitapara, Vivek S. Patel, and Daniel J. Antoine have not responded to any correspondence from the editor/publisher about this editorial expression of concern.
Reference
Sitapara, et al. The α7 nicotine acetylcholine receptor agonist GTS-21 improves bacterial clearance in mice by restoring hyperoxia-compromised macrophage function. Mol Med. 2014;20:238–47 https://molmed.biomedcentral.com/articles/10.2119/molmed.2013.00086.
Interesting development… The MRC Centre for Drug Safety Science (at which Daniel Antoine was based in Liverpool) has just publicised the findings of a clinical trial, detailed below:
https://www.liverpool.ac.uk/mrc-centre-for-drug-safety-science/news/stories/title,1188255,en.html
McWilliam SJ, Rosala-Hallas A, Jones AP, Shaw V, Greenhalf W, Jaki T, Smyth AR, Smyth RL, Pirmohamed M. A randomised controlled trial of rosuvastatin for the prevention of aminoglycoside-induced kidney toxicity in children with cystic fibrosis. Sci Rep. 2020;10(1):1796. Published 2020 Feb 4. doi:10.1038/s41598-020-58790-1
The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n=23, control n=27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n=20, control n=24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87–1.35, p=0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.
The important link here is that Daniel Antoine appears to have led the initial preclinical study that provided the foundation for the more recent clinical work.
Antoine DJ, Srivastava A, Pirmohamed M, Park BK. Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells. Biochem Pharmacol. 2010;79(4):647–654. doi:10.1016/j.bcp.2009.09.021
And he has co-authored papers on the subject with the first and last authors of the clinical trial paper:
McWilliam SJ, Antoine DJ, Smyth RL, Pirmohamed M. Aminoglycoside-induced nephrotoxicity in children. Pediatr Nephrol. 2017;32(11):2015–2025. doi:10.1007/s00467-016-3533-z
McWilliam SJ, Antoine DJ, Pirmohamed M. Repurposing Statins for Renal Protection: Is It a Class Effect?. Clin Transl Sci. 2018;11(2):100–102. doi:10.1111/cts.12521
This raises two important questions:
1. Is any of the data in the original Biochem Pharmacol paper fraudulant? Is it part of Liverpool University’s investigation?
2. Was it this paper that provided enough confidence for the UK regulator to approve what turned out to be an unsuccessful clinical trial, in which children were exposed to rosuvastatin and its associated adverse effects?
All of the retractions so far seem to relate to HMGB1, but a broader investigation seems very appropriate. More to be revealed, I’m sure!
2020 retraction for:
J Hepatol . 2012 May;56(5):1070-1079.
doi: 10.1016/j.jhep.2011.12.019. Epub 2012 Jan 17.
Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity
Daniel J Antoine 1, Rosalind E Jenkins 2, James W Dear 3, Dominic P Williams 2, Mitchell R McGill 4, Matthew R Sharpe 5, Darren G Craig 6, Kenneth J Simpson 6, Hartmut Jaeschke 4, B Kevin Park 2
Affiliations collapse
Affiliations
1MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK. Electronic address: [email protected].
2MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
3University/BHF Centre for Cardiovascular Science, Edinburgh University & NPIS Edinburgh, Scottish Poisons Information Bureau, Edinburgh, UK.
4Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
5Department of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
6Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
2020 retraction. https://www.journal-of-hepatology.eu/article/S0168-8278(20)33554-6/fulltext
This article has been retracted at the request of the Editor-in-Chief and Authors. Concerns were raised by one of the Co-Authors and the University of Liverpool regarding the reliability and replicability of the research undertaken into the HMGB1 isoforms, including their potential use to inform mechanisms, diagnosis and prognosis of various disease states. After numerous subsequent analyses, the assays and data for cytokeratin 18 and total HMGB1 have proven to be reproducible, either from direct reanalyses or from parallel studies. The Authors were able to re-analyse a subset of 35 original clinical samples for total HMGB1 (using the same commercial ELISA assay as that used in the paper) and found a strong correlation with the original data. We have re-analysed clinical samples from a separate paracetamol overdose patient cohort for these markers (and reported in a separate paper, Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies; J.W. Dear, J.I. Clarke, B. Francis, L. Allen, J. Wraight, J. Shen, et al.; Lancet Gastroenterol Hepatol. 2018 Feb; 3(2):104-113 PMID: 29146439). The analyses again showed a strong correlation. Furthermore, the repeat keratin 18 analyses from this second cohort, together with separate work by one of the paper’s co-authors, Dr Ken Simpson, on a study of acute liver failure patients following paracetamol overdose (Circulating apoptotic and necrotic cell death markers in patients with acute liver injury; D.G.N. Craig, P. Lee, E.A. Pryde, G.S. Masterton, P.C. Hayes, K.J. Simpson; Liver International, 31(8) (2011) pp. 1127-1136 PMID: 21745283) replicated the findings for both forms of this biomarker. The Authors are therefore confident that the bioanalytical readouts and clinical implications from the original total HMGB1, caspase-cleaved keratin 18 and total keratin 18 data are correct. However, in respect to acetylated HMGB1, after various approaches and reanalyses the methodology cannot be reproduced as described in the paper and therefore the authors and the University of Liverpool have been unable to verify whether the data for this analyte are correct and reproducible. The method for acetylated HMGB1 quantification has two main components: isolation of the HMGB1 analyte from clinical samples using immunoprecipitation and subsequent protein digestion and mass spectrometric analysis of the HMGB1 peptides. The Authors are confident that the mass spectrometry protocol is robust but they have been unable to recapitulate the immunoprecipitation and digestion. They are working on new methods, with collaborators, to identify all HMGB1 isoforms. As a consequence of the above, and the central importance of the acetylated HMGB1 data to the scientific trustworthiness, the decision has been made to retract the paper.