2024-26756. Findings of Research Misconduct C

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Department of Veterans Affairs

AGENCY:

Department of Veterans Affairs.

ACTION:

Notice.

SUMMARY:

The Department of Veterans Affairs (VA), gives notice, pursuant to Veterans Health Administration (VHA) Directive 1058.02 “Research Misconduct” section 8.l, that the Department has made findings of research misconduct against Alan Lichtenstein, M.D. (“Respondent”), a former staff physician at the VA Greater Los Angeles Healthcare System, Los Angeles, CA. The Respondent did not appeal the findings or corrective actions against him.

FOR FURTHER INFORMATION CONTACT:

Shara Kabak, Research Misconduct Officer, Office of Research Oversight (10RO), 810 Vermont Avenue NW, Washington, DC 20420, [phone] (this is not a toll-free number).

SUPPLEMENTARY INFORMATION:

VA has made final findings of research misconduct against Alan Lichtenstein, M.D. (“Respondent”), a former staff physician at the VA Greater Los Angeles Healthcare System in Los Angeles, CA.

Based on the recommended findings of a joint investigation conducted by VA Greater Los Angeles Healthcare System and University of California, Los Angeles School of Medicine, the Department found that the Respondent engaged in research misconduct by recklessly falsifying data included in at least ten of the following thirteen published papers:

• DEPTOR is linked to a TORC1-p21 survival proliferation pathway in multiple myeloma.Genes & Cancer. 2014 Nov;5(11-12):407-19. doi: 10.18632/genesandcancer.44 (hereafter, “ Genes Cancer 2014”).
• Cytotoxic properties of a DEPTOR-mTOR inhibitor in multiple myeloma cells.Cancer Research. 2016 Oct 1;76(19):5822-5831. doi: 10.1158/0008-5472. CAN-16-1019 (hereafter, “ Cancer Res. 2016 ”).
• Interleukin-6 activates phosphoinositol-3 kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways.Oncogene. 2004 Apr 22;23(19):3368-75. doi: 10.1038/sj.onc.1207459 (hereafter, “ Oncogene 2004”).
• MNK1-induced eIF-4E phosphorylation in myeloma cells: a pathway mediating IL-6-induced expansion and expression of genes involved in metabolic and proteotoxic responses.PLoS One. 2014 Apr 8;9(4):e94011. doi: 10.1371/journal.pone.0094011 (hereafter, “ PLoS One 2014 ”). Retraction in: PLoS One. 2023 Sep 8;18(9):e0291491. doi: 10.1371/journal.pone.0291491.
• Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade.Molecular Cancer Therapeutics. 2005 Oct;4(10):1533-40. doi: 10.1158/1535-7163.MCT-05-0068 (hereafter, “ Mol Cancer Ther. 2005”).
• Inhibition of SAPK2/p38 enhances sensitivity to mTORC1 inhibition by blocking IRES-mediated translation initiation in glioblastoma.Molecular Cancer Therapeutics. 2011 10:2244-2256 Dec;10(12):2244-56. doi: 10.1158/1535-7163.MCT-11-0478 (hereafter, “ Mol Cancer Ther. 2011 ”).
• Specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma.PLoS One. 2017; Apr 28;12(4):e0176599. doi: 10.1371/journal.pone.0176599 (hereafter, “ PLoS One 2017 ”). Correction in: PLoS One. 2019 Feb 6;14(2):e0212160. doi: 10.1371/journal.pone.0212160. Retraction in: PLoS One. 2023 Sep 8;18(9):e0291490. doi: 10.1371/journal.pone.0291490.
• MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma.Oncogene. 2013 Jan 10;32(2):190-7. doi: 10.1038/onc.2012.43 (hereafter, “ Oncogene 2013 ”). Expression of Concern in: Oncogene. 2023 Oct;42(41):3088. doi: 10.1038/s41388-023-02818-z.
• The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/eukaryotic translation initiation factor 4E (eIF-4E)/RAF pathway and activation is a mechanism of resistance.Journal of Biological Chemistry. 2012 Jun 22;287(26):21796-805. doi: 10.1074/jbc.M111.304626 (hereafter, “ J Biol Chem. 2012 ”).
• Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress.Oncogene. 2016 Feb 25;35(8):1015-24. doi: 10.1038/onc.2015.156 (hereafter, “ Oncogene 2016 ”). Retraction in: Oncogene. 2023 Sep;42(40):3016. doi: 10.1038/s41388-023-02820-5.
• SGK kinase activity in multiple myeloma cells protects against ER stress apoptosis via a SEK-dependent mechanism.Molecular Cancer Research. 2016 Apr;14(4):397-407. doi: 10.1158/1541-7786.MCR-15-0422 (hereafter, “ Mol Cancer Res. 2016 ”).
• A novel therapeutic induces DEPTOR degradation in multiple myeloma cells with resulting tumor cytotoxicity.Molecular Cancer Therapeutics. 2019 Oct;18(10):1822-1831. doi: 10.1158/1535-7163.MCT-19-0115 (hereafter, “ Mol Cancer Ther. 2019”).
• Downstream effectors of oncogenic ras in multiple myeloma cells.Blood. 2003 Apr 15;101(8):3126-35. doi: 10.1182/blood-2002-08-2640 (hereafter, “ Blood 2003”).

Specifically, the Department found that the Respondent recklessly committed research misconduct by reusing the same Western blot or kinase assay image to falsely represent the results related to the following pairs of experiments such that at least one of the sets of images in each of the pairs listed below is inaccurate:

• p-4E-BP1-T37/46, p-4E-BP1-S65 and Tubulin expression in Figure 3B ofGenes Cancer 2014 and Figure 1F of Cancer Res. 2016. ( print page 90834)
• P-AKT-S473 expression in Figure 3C inGenes Cancer 2014 and lanes 1-4 of DEPTOR expression in Figure 3C of Cancer Res. 2016 with resizing.
• Lanes 7-9 of p70S6K1 expression in Figure 1A ofGenes Cancer 2014 and DEPTOR expression in Figure 4C of Cancer Res. 2016.
• STAT3 associated kinase activity in Figure 4A and lanes 1-4 of p110 mu associated kinase activity in Figure 5B ofOncogene 2004.
• Lanes 7-8 of ACTIN expression in Figure 1A and lanes 7-8 of ACTIN expression in Figure 1C ofPLoS One 2014.
• Lanes 3-4 of P-MNK and T-MNK expression in Figure 1C ofPloS One 2014 and lanes 1-2 of FKHD-P and FKHD-T expression (top panels) in Figure 1B of Mol Cancer Ther. 2005.
• Lanes 4-8 of P-AKT (S473) and actin expression in Figure 2A ofMol Cancer Ther. 2011 and AKT and S6K expression in Figure 1F of PloS One 2017 with a 180 degree rotation of the P-AKT/AKT panels.
• Lanes 1-2 of T-HSP27 expression and lanes 4-5 of GAPDH expression in Figure 2B ofOncogene 2013.
• Lanes 1-3 of p-erk and lanes 2-4 of t-erk expression in Figure 3B and lanes 1-3 of erk(T202/Y204) and erk expression in Figure 4A ofJ Biol Chem. 2012.
• α-tubulin expression in Figure 4D and 4E ofGenes Cancer 2014.
• C-myc expression in Figure 1B and lanes 1-4 of T-p70 expression in Figure 1E ofOncogene 2016.
• T-4E-BP1 (α, β and γ phosphorylated forms) expression (middle panel) and lanes 1-4 of T-4E-BP (α, β and γ phosphorylated forms) expression (right panel) of Supplemental Figure 2A ofOncogene 2016.
• T-S6 expression and C-myc expression in Figure 1F ofOncogene 2016.
• Lanes 2-5 of MNK-P and MNK-T expression (left panel) in Figure 3A and ERK-T and Hsp-27-T expression in Figure 4A ofOncogene 2016.
• MNK1, MNK2 and GAPDH expression in Figure 3E ofOncogene 2016 and MNK1, MNK2 and GAPDH expression in Figure 3A of PloS One 2014.
• ire-1-total expression (right panel) in Figure 5B ofMol Cancer Res. 2016 and mTor expression in Figure 8A of Genes Cancer 2014 with resizing.
• The right panel of ACTIN expression in Figure 2A and the right panel of ACTIN expression in Figure 2g ofMol Cancer Ther. 2019.
• Lanes 1-6 of DEPTOR and mTOR expression in Figure 1A ofGenes Cancer 2014 and DEPTOR and mTor expression in Figure 6A of Mol Cancer Ther. 2019.
• IRS-1 expression in lanes 4-5 and lanes 8-9 in Figure 6B ofMol Cancer Ther. 2005.
• AKT expression (bottom panel) in Figure 1Aand lanes 7-9 of IRS-1 expression in Figure 6B ofMol Cancer Ther. 2005.
• Lanes 4-6 of IGF-R expression and lanes 4-6 of FLAG expression in Figure 5B ofMol Cancer Ther. 2005 with a 180-degree rotation.
• Lanes 2-3 of AKT-T expression (4th panel) in and lanes 1-2 of AKT-T expression (6th panel) in Figure 1C ofMol Cancer Ther. 2005.
• Lanes 1-2 of AKT-P expression (top panel) and lanes 1-2 of AKT-P expression (5th panel) in Figure 1E ofMol Cancer Ther. 2005.
• Lanes 1-3 and lanes 5-7 of FKH-T expression in Figure 3C ofBlood 2003.
• Lane 1 of p70 expression and Ser411 expression in Figure 4B and lane 4 of Ser411 expression and lanes 1-2 of Ser411 expression in Figure 4c ofBlood 2003.
• Lanes 1 and 3 of ERK-P expression and lanes 2 and 4 of ERK-T expression in Figure 2C ofBlood 2003.

Based on these findings of research misconduct, which the Respondent did not appeal, the Department has imposed the following corrective actions:

(1) Prohibition from conducting VA research for at least 2 years;

(2) Notification to the relevant journals of the research misconduct findings.

Signing Authority

Denis McDonough, Secretary of Veterans Affairs, signed and approved this document on November 12, 2024, and authorized the undersigned to sign and submit the document to the Office of the Federal Register for publication electronically as an official document of the Department of Veterans Affairs.

Jeffrey M. Martin,

Assistant Director, Office of Regulation Policy & Management, Office of General Counsel, Department of Veterans Affairs.