Following five years of criticism, a group of researchers based at Stanford and elsewhere have retracted a 2006 paper in Nature for “image anomalies.”
The notice for “Lysyl oxidase is essential for hypoxia-induced metastasis” reads:
We, the authors, are retracting this Article owing to issues that have come to our attention regarding figure assembly and data availability. Image analysis of the data has showed several image anomalies in Fig. 4c, Supplementary Figs. 1a, e and 4a. Nature has informed us that the quality and integrity of these images are not in line with journal policies. In particular, the panels affected include Supplementary Fig. 4a, which demonstrates that the shRNA construct used in the manuscript induces a reduction of LOX protein. No original data are available for the affected panels or other data included in the manuscript. We believe that the key findings of the paper are still valid as replicated by others. However, given the issues described above and the absence of original data, we have concluded that the most appropriate course of action is to retract the Article. All authors agree with the Retraction.
Comments about the paper first appeared on PubPeer in 2015. Over the ensuing years first author Janine Erler’s ex-husband Rune Linding, also a scientist, and a colleague of Linding’s commissioned independent analyses of the images in the papers. Those analyses found potential duplications and splicing, as we reported in 2018.
The paper has been cited 960 times, according to Clarivate Analytics’ Web of Science, and 62 of those citing papers were designated “highly cited papers.” Of the 960 citations, 134 appeared since March 2018.
Asked to comment on the retraction, first author Erler, now of the University of Copenhagen, sent us the following comment, writing that “You may use the following quote in full – I do not agree to partial use.”
As stated in the retraction text, Nature informed us that some of the images in the paper were not in line with their policies. Due to the age of the paper, we lacked the original data and therefore felt the appropriate action was to retract the paper. The paper is highly cited (961 citations) and the findings highly reproduced by other researchers. We therefore stand by the scientific findings. Importantly, this paper had nothing to do with the development, testing or clinical trials of the LOXL2 targeting antibody Simtuzumab.
The paper was one of more than 400 references cited in a patent application to develop inhibitors of enzyme lysyl oxidase (LOX) enzymes to prevent and treat cancer metastases. Gilead abandoned that approach in 2016 after failed trials. But Steven D. Nathan, director of the Advanced Lung Disease Program and director of the Lung Transplant Program at Inova Fairfax Hospital, told us in 2018 that he “highly doubt[ed] the company developed this based on one study. I think it probably would have been developed anyway.”
In 2018, Nature told us that it was “following an established process to investigate the issues” but could not comment on the ongoing investigation. We asked Nature why it was taking action now. A spokesperson told us:
In general, whenever concerns are raised about papers we have published, whether by the original authors or by other researchers and readers, we look into them carefully, following an established process, consulting the authors and, where appropriate, seeking advice from peer reviewers and other external experts. Once this process has concluded and we have the necessary information to make an informed decision, we will follow up with the response that is most appropriate in order to maintain the accuracy of the scientific record. These issues are often complex, however, and as a result, it can take time for editors and authors to fully unravel them.
In addition to the retraction, Erler has had two papers corrected and one subject to an expression of concern. The EOC, in Cancer Research, reads:
The editors were made aware of concerns regarding this article (1). An internal review by the editors determined that lanes 2–4 of the pSMAD2 Western blot image in Supplementary Fig. S3C are identical to the LOX Western blot image in Supplementary Fig. S3D.
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“The paper is highly cited (961 citations) and the findings highly reproduced by other researchers. We therefore stand by the scientific findings.”
Erler must mean the scientific findings by other researchers because there are no scientific findings in her retracted Nature paper. A career in predicting future scientific findings seems the way to go.
https://www.nature.com/articles/nature04695#author-information
Senior author, and the corresponding author, of the retracted Nature paper might check the data in this paper.
Nat Med. 2013 Oct;19(10):1325-30. doi: 10.1038/nm.3294. Epub 2013 Sep 15.
Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes.
Taniguchi CM1, Finger EC, Krieg AJ, Wu C, Diep AN, LaGory EL, Wei K, McGinnis LM, Yuan J, Kuo CJ, Giaccia AJ.
Author information
1
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford, California, USA.
Figure 4.
https://pubpeer.com/publications/FB7695753BB37D69E5FC65189D8B5D#6
Senior and corresponding author is presently DIRECTOR, OXFORD INSTITUTE FOR RADIATION ONCOLOGY
https://www.oncology.ox.ac.uk/team/amato-giaccia
Cancer Res. 2000 Aug 15;60(16):4638-44.
p53 promotes selection for Fas-mediated apoptotic resistance.
Maecker HL1, Koumenis C, Giaccia AJ.
Author information
1
Department of Radiation Oncology, Stanford University Medical Center, California 94305-5468, USA.
Figure 10B. Much more similar than you would expect.
See: https://imgur.com/FLTy3o5
Figure 1.
See: https://pubpeer.com/publications/7F21F81808440F0817C8569B262A34#5
Sci Transl Med. 2014 May 14;6(236):236ra64. doi: 10.1126/scitranslmed.3008523.
PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2.
Taniguchi CM1, Miao YR1, Diep AN1, Wu C1, Rankin EB1, Atwood TF1, Xing L1, Giaccia AJ2.
Author information
1
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
2
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Figure 5A.
The two bands are much more similar than you would expect, i.e. not that they are completely the same , but that they are unlikely to come from different origins. The lack of background does make a difference because you can move bands around without any trace.
https://imgur.com/uv554lu
Cancer Cell. 2005 Dec;8(6):443-54.
The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation.
Bedogni B1, Welford SM, Cassarino DS, Nickoloff BJ, Giaccia AJ, Powell MB.
Author information
1
Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA.
Figure 5B.
https://imgur.com/eG4zgFm
Genes Dev. 2000 Feb 15;14(4):391-6.Loss of PTEN facilitates HIF-1-mediated gene expression.Zundel W1, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ.Author information1Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University, Stanford, California 94305-5468 USA.
Figure 5D. Much more similar than you would expect.
See: https://imgur.com/JiGXD4z
Mol Cell Biol. 2002 Mar;22(6):1834-43.Hypoxia links ATR and p53 through replication arrest.Hammond EM1, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ. Author information1Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94303-5152, USA.
Figure 2. Much more similar than you would expect.
https://imgur.com/gtn0UOb
J Clin Invest. 2008 Nov;118(11):3660-70. doi: 10.1172/JCI36157. Epub 2008 Oct 16.Notch1 is an effector of Akt and hypoxia in melanoma development.Bedogni B1, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB.Author information1Division of Radiation and Cancer Biology, Stanford University, Stanford, California, USA.
Figure 2A. Much more similar than you would expect after horizontal re-sizing.See: https://imgur.com/WAKxjbt
Figure 1B. apparent splicing in some panels, but not in other panels, making comparisons between panels problematic.See: https://imgur.com/bga6EvX
Genes Dev. 1998 Jul 1;12(13):1941-6.Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress.Zundel W1, Giaccia A.Author information1Cancer Biology Program, Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5468 USA.
Figure 5A. Much more similar than you would expect after horizontal flipping.
See: https://imgur.com/GjF8soR
17 April Retraction for Janine Erler.
https://www.nature.com/articles/s41586-023-06048-x