Xiongbin Lu nanobombs cancer with fluorescent nude mouse recycling

Cancer research breakthrough! A “game-changer treatment” was announced by the Indiana University in Indianapolis, USA, in February 2021:

“A team of Indiana University School of Medicine researchers has developed a novel antibody-drug conjugate for treating triple negative breast cancer.

The study, led by senior author Xiongbin Lu, Vera Bradley Foundation Professor of Breast Cancer Innovation at the IU School of Medicine, has been published in the prestigious interdisciplinary medical journal, Science Translational Medicine. […]

Lu said developing T-Ama has been a team effort, as researchers at the Vera Bradley Foundation Center for Breast Cancer Research — such as Xinna Zhang, Dr. Bryan Schneider, Milan Radovich and Dr. Kathy Miller — have collaborated with Heidelberg Pharma, a German pharmaceutical company. […]

Lu is co-leading a cancer immunotherapy program for triple negative breast cancer as part of the IU Precision Health Initiative. Zhang is also involved in the initiative for developing novel breast cancer immunotherapy.”

Amazing research by Dr Lu, bringing hope for breast cancer patients. The Vera Bradley Foundation is a charity which seeks to save women’s lives by sponsoring mammary cancer research. It recruited Lu in 2017, as this press release announced:

“Dr. Lu currently is the principal investigator of four National Institutes of Health-funded projects, and many of his scientific papers have been published in prestigious journals such as Nature, Cancer Cell, Molecular Cell, and Nature Communications.

Previously, Dr. Lu was an associate professor in the Department of Cancer Biology at the University of Texas M.D. Anderson Cancer Center in Houston. Earlier he held positions at the University of South Carolina in Columbia and Baylor College of Medicine in Houston.”

Strange the Indiana University press release never hinted that Xinna Zhang is Xiongbin Lu’s wife, why is it a secret now, a 2019 press release celebrated their combined family genius. Another 2019 press release about Lu’s research predicted an upcoming “nanobomb” cure for triple-negative breast cancers. Which now arrived, behold:

Yujing Li, Yifan Sun, Michael Kulke, Torsten Hechler, Kevin Van Der Jeught, Tianhan Dong, Bin He, Kathy D. Miller, Milan Radovich, Bryan P. Schneider, Andreas Pahl, Xinna Zhang, Xiongbin Lu Targeted immunotherapy for HER2-low breast cancer with 17p loss Science Translational Medicine (2021) doi: 10.1126/scitranslmed.abc6894

And this is what that “game-changer” paper contained:

Recycled images, used for differently treated mice. The images are shifted, which hardly can happen by mistake of oversight. And lets you wonder what all other images in that figure really show. Lu replied immediately on PubPeer:

“We apologize for this unintended and inadvertent error. We are submitting an Erratum to the journal to correct our error.“

A month before, a press release by the Vera Bradley Foundation celebrated a breakthrough in breast cancer immunotherapy, a great return on the charity’s investment into the research of Drs Lu and Zhang:

“Like other cancer cells, breast cancer cells present tumor-specific antigens on the cell membrane, which immune cells recognize so they can kill the tumor cells,” Zhang said. “But our study found that MAL2 can reduce the level of these antigens, so these tumor cells are protected and can no longer be recognized as a threat by these immune cells.”

The tumour cells are not the only ones hiding, there are also hidden data irregularities in that paper.

Hanchen Xu, Kevin Van Der Jeught, Zhuolong Zhou, Lu Zhang, Tao Yu, Yifan Sun, Yujing Li, Changlin Wan, Kaman So, Degang Liu, Michael Frieden, Yuanzhang Fang, Amber L. Mosley, Xiaoming He, Xinna Zhang, George E. Sandusky, Yunlong Liu, Samy O. Meroueh, Chi Zhang, Aruna B. Wijeratne, Cheng Huang, Guang Ji, Xiongbin Lu Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation Journal of Clinical Investigation (2021) doi: 10.1172/jci146832

Lu, his wife and another colleague declared in this publication to have submitted a patent in this regard. For what, fluorescent nude mouse recycling? Actually, good idea, it is very reproducible, not just for breast, but also for other cancers. Here, Ewing sarcoma and bladder cancer:

Yunhua Liu, Hanchen Xu, Kevin Van Der Jeught, Yujing Li, Sheng Liu, Lu Zhang, Yuanzhang Fang, Xinna Zhang, Milan Radovich, Bryan P. Schneider, Xiaoming He, Cheng Huang, Chi Zhang, Jun Wan, Guang Ji, Xiongbin Lu Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer Journal of Clinical Investigation (2018) doi: 10.1172/jci98727  

Accompanied by a reused, shifted, and slightly brightened immunohistochemistry image, to stand in for tissues of differently treated mice:

Fluorescent nude mouse recycling also proved reproducible for ovarian cancer, the technology worked already at Dr Lu’s previous place of work, MD Anderson in Houston, Texas:

Did you notice the celebrity coauthor? Anil Sood! The ovarian cancer data fabricator (read here and here) whose continuing employment and whose institutional power at MD Anderson in Texas make you think that giant research hospital in Houston was almost a criminal organisation akin to mafia, its whole purpose being to defraud public money? Right now, Sood is the leader of MD Anderson’s Ovarian Cancer Moon Shit Shot program.

Sood is a greedy man, for money, power and fame. As insiders tell me, he operates patients until 5 PM. Filled up on cash, he pops over to his huge research lab for a quick round, where he briefly glances over what his minions have produced and warns them that they need to generate results faster in order to publish in the big journals. The results of this leadership style are observable on PubPeer, currently over 50 papers.

Lu claimed on PubPeer that he and his coauthors “noticed it after the paper was published” and also:

“We did communicate with the handling editor of Cell Reports and sent a corrigendum to the journal immediately after the error was found. As I recalled, we never received a reply.”

As reminder, Lu arrived to his high-ranking and charity-funded position at the Indiana University from MD Anderson, where he collaborated with Sood, with his wife in tow (Lu’s wife, not Sood’s). The paper which cinched the Indiana appointment for Lu and Zhang was this one, of course in Nature. For toxic completeness, it has not only Sood on it, but also Sood’s close associate, Gabriel Lopez-Berestein:

Yunhua Liu, Xinna Zhang, Cecil Han, Guohui Wan, Xingxu Huang, Cristina Ivan, Dahai Jiang, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Pulivarthi H. Rao, Dipen M. Maru, Andreas Pahl, Xiaoming He, Anil K. Sood, Lee M. Ellis, Jan Anderl, Xiongbin Lu TP53 loss creates therapeutic vulnerability in colorectal cancer Nature (2015) doi: 10.1038/nature14418

If you believe these peculiar image duplications are an innocent mistake of oversight, I have a magic cancer cure to sell you. By the way: the authors patented the therapeutic approach described in this paper, but forgot to declare any conflicts of interests beyond “J.A. and A.P. are employees of Heidelberg Pharma GmbH“. As Cheshire (who posted much of the other PubPeer evidence for Lu papers) noticed, the patent “Methods of treating cancer harboring hemizygous loss of tp53” was filed on 4 March 2015 and registered to Xiongbin Lu and Yunhua Liu, the Nature paper was accepted on 15 March 2020. Basically, the first and last authors hid their patent COI.

Remember the anti-cancer nanobomb Lu developed? You might wonder what it is. The university press release explains:

“Lu’s nanobomb is a pair of cancer drugs—one already in use and another experimental—wrapped in a package that helps it travel safely through the bloodstream. Once it reaches cancer cells, the nanobomb is ushered inside through the natural process of how cells eat—endocytosis. The acidity of its new environment triggers the nanobomb, causing it to expand—anywhere from 100 to 1,000 times its original size. Under the strain, the bomb’s package breaks apart, and the two drugs are released to kill the cancer cell.”

Basically, common chemotherapeutics, but also drugs which proved disappointing when first touted as cancer cures, can be repackaged into something with nanotechnology on it, and suddenly become very fancy and advanced. One of Lu’s R01 grants is titled “Nanotechnology enabled targeting of p53 deficiency in human cancer“. Because nothing worked on targeting p53 deficiency in cancers so far, nanotechnology will. If applied creatively, that is. Like here:

Hai Wang, Pranay Agarwal, Gang Zhao, Guang Ji, Christopher M. Jewell, John P. Fisher, Xiongbin Lu, Xiaoming He Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial ACS Central Science (2018) doi: 10.1021/acscentsci.8b00050

The nanobomb is so powerful it can even set off fluorescent nude mouse recycling events!

Hai Wang, Pranay Agarwal, Shuting Zhao, Jianhua Yu, Xiongbin Lu, Xiaoming He A biomimetic hybrid nanoplatform for encapsulation and precisely controlled delivery of theranostic agents. Nature Communications (2015) doi: 10.1038/ncomms10081 

So the sedated mice moved a bit during the first 6 hours, then returned into exactly the same initial position they were at the very beginning? How credible is that, and what did really go on there?

Very recently, the fluorescent nude mouse recycling nanobomb went off at Nature Communications again:

Something is off with the T0h mice, they seem to get duplicated. Lu commented on PubPeer:

“Thank you very much for the comments! I’ll talk to my co-authors and carefully address them ASAP. Best regards!“

More on the topic of nanobombing the triple-negative breast cancer, without the recycled mice but again with the regular co-author Xiaoming He at the University of Maryland:

Jiangsheng Xu, Yunhua Liu, Yujing Li, Hai Wang, Samantha Stewart, Kevin Van Der Jeught, Pranay Agarwal, Yuntian Zhang, Sheng Liu, Gang Zhao, Jun Wan, Xiongbin Lu, Xiaoming He Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer Nature Nanotechnology (2019) doi: 10.1038/s41565-019-0381-6 

The last author He, who a year ago shared a R01 grant with Lu, blamed on Pubpeer “the student” for everything and announced a correction, which promptly happened.

Lu’s wife Zhang published a last author paper 3 years ago, together with her husband and their Maryland colleague He:

Yunhua Liu, Jiangsheng Xu, Hyun Ho Choi, Cecil Han, Yuanzhang Fang, Yujing Li, Kevin Van Der Jeught, Hanchen Xu, Lu Zhang, Michael Frieden, Lifei Wang, Haniyeh Eyvani, Yifan Sun, Gang Zhao, Yuntian Zhang, Sheng Liu, Jun Wan, Cheng Huang, Guang Ji, Xiongbin Lu, Xiaoming He, Xinna Zhang Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer Nature Communications (2018) doi: 10.1038/s41467-018-07264-0 

Something is wrong with this tumour array:

It seems, the image is a composite one, some (or most, or maybe even all) tumours were inserted digitally. Which defies the whole purpose of this figure, where the reader is invited to judge the relative as well as the absolute tumour size, look, even a ruler is placed there for that purpose. When you assemble the picture like the authors did, the reader cannot trust the alleged size relations anymore. Or anything else in that paper, quite possibly.

Both Lu and his wife are funded not only by Vera Bradley Foundation, but also by yet another cancer charity, Chuckstrong, which focusses on leukaemia. The Indiana University invites you to donate.

Those were the new findings in Lu papers, mostly spotted by Cheshire. But there is older stuff. Like this 11 year old paper which festers on PubPeer for already 4 years.

Sung-Hwan Moon, Lin Lin, Xinna Zhang, Thuy-Ai Nguyen, Yolanda Darlington, Alan S. Waldman Xiongbin Lu, Lawrence A. Donehower Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair The Journal of biological chemistry (2010) doi: 10.1074/jbc.m109.071696

Back in the days, scientists still relied on western blots, which is a robust technology very difficult to fake convincingly. This is also why PubPeer is full of western blot evidence of data manipulation, other lab methods are much less accessible for sleuthing. Here another old western blot classic, also from the lab of Lu’s mentor Lawrence Donehower at Baylor College of Medicine in Houston, on PubPeer for 3 years already:

Xiongbin Lu, Ou Ma, Thuy-Ai Nguyen, Stephen N. Jones, Moshe Oren, Lawrence A. Donehower The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop Cancer Cell (2007) doi: 10.1016/j.ccr.2007.08.033

First, there was undisclosed gel splicing:

One of the authors (maybe even Lu?) anonymously replied already in August 2017:

“In the figures, we only used the part of immunoblotting images for those further used siRNAs and cut off the image of other siRNAs. This explains the obvious edges on the blotting images. To best compare the effect of Wip1 on the ubiquitination of p53 and Mdm2, all the ubiquitinated protein samples were run on the same gel and blotted on the same membrane, as shown in these figures.”

Only that this is not true. Only Wip1 gels are spliced, the other gels are not, which means the authors either run separate gels without internal loading control, or, if they did, they replaced the results, hence the hidden splicing. There was another issue:

It is clearly the same gel image. But the same anonymous author insisted:

“this was the immunoblotting results by using p53 and p53(pS18) antibody, respectively, on the same transferred membrane. Due to the extremely low levels of p53 and its phosphorylated form in MEFs without stress (irradiation), the western blots appear almost the same, but that is what the result was.“

Even assuming a stripped and re-probed gel would provide an identical image (which it never would), a critic was appalled:

“Why on earth would you blot for total p53 before phospho p53? Did you reverse the blotting order on a fresh run to check it was a bona fide result?“

Good point, which suggest the authors may have been doing their science backwards at best. But this is the science-fiction publisher Cell Press for you, where the only editorial request is for the authors to be preferably from USA and the results to be piping hot (Wip1 is a cancer cure target!), never mind how you achieved those. In Cell journals, you don’t have to prove wookiees exist, you only need to draw a pretty enough picture of Chewbacca.

I asked Lu about all these shenanigans in his papers. He replied:

“Thank you for reaching out. Scientific integrity is essential to our research. Yes, we will address all the concerns/errors as soon as possible.”

He didn’t answer the question if there will be investigation. But Indiana University Research Integrity Officer Shelley Bizila did:

“My office, IU’s Research Integrity Office, is responsible for receiving any allegations of possible falsification, fabrication or plagiarism and for administering IU’s policy.  As such, our office has previously been made aware of the concerns you cite and has already started an inquiry process.  We will proceed according to our policy to ensure any concerns of possible research misconduct are addressed. “

In between, Lu’s influence in Indiana increased, his preclinical research with nanobombing fluorescent nude mouse recycling is about to be translated into clinical trials.

Xiongbin Lu named co-program leader of EDT research program at IU Simon https://t.co/EN1rJTyH5H @IUMedSchool pic.twitter.com/4ZlTLwOns8

— The Cancer Letter (@TheCancerLetter) March 16, 2021

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