Research integrity University Affairs

Oral oncology at Showa University

""Dear Aneurus Inconstans, thank you for your series of valuable suggestions. We will sincerely verify the matters pointed out. I'm sorry, many collaborators have already resigned from academia."

Japan certainly could use more coverage on For Better Science. Luckily, Aneurus Inconstans is there to help, and brings you a story of some long-retired Japanese dentists and oral oncologists, and their fake papers which nobody bothers to retract.

Research fraud is big in Japan. Some of the biggest scandals happened there: the STAP stem cell farce of Haruko Obokata (my own entry into research fraud journalism!), the Yoshinori Watanabe forgeries (his foreign peers did their best to save his career), and then of course, as per Retraction Watch leaderboard: the many hundreds of utterly fabricated studies by the anaesthesiology researchers Yoshitaka Fujii (183 retractions), Hironobu Ueshima (117 retractions) and Yuhji Saitoh (53 retractions), by the deceased bone researcher Yoshihiro Sato (106 retractions), by the endocrinologist Shigeaki Kato (40 retractions) and by the virologist Naoki Mori (31 retractions) .

So what did Japan learn from these affairs? Not much. If the media attention gets too much, the fraudster might be asked to resign. There is still no national research integrity authority (and no plans to create one either), the national science funding agencies are toothless and/or couldn’t give less of a toss, and the universities sometimes literally outsource the investigations to the fraudsters themselves.

Let me remind you of a recent case, of the one-man papermill and PhD graduate of the Hokkaido University, Ahmed Shalan (read here and here). Shalan is presently being investigated by his current employer in Spain, yet several of his earlier fabrications were supervised by the Hokkaido pumpkin professor Hiroaki Misawa.

A reader tried to reach out to the University of Hokkaido after Misawa ignored all emails. The reader had to recruit the help of a Japanese speaker to find the right email contact. Turned out, he had to send a report to the Sakamoto/Matsuda Law Office (Hokkaido’s Consultation Counter for Accusations), yet also this email went unanswered. After a reminder, the law office replied to my reader on behalf of the university:

I have not notified the whistleblower that the university will not accept it because it does not meet the requirements.

My reader did not give up. He submitted a more formal report using the university’s Japanese language template. You probably would like to know how the Hokkaido University reacted?

Misconduct in research is a matter of concern to Hokkaido
University and we take seriously all allegations of misconduct.


In reply to your request to investigate a doctoral thesis by
Mr. Shalan and your indications on his three other scientific
papers, we would like to inform you that we have learned that
he and his co-authors are aware of the issues posted on the
PubPeer website, and that they are currently in discussions.
We therefore will not be investigating his papers for the
time being.


Provided that he and/or his former mentor recognize possible
wrongdoing(s) in his dissertation, an investigation will be
initiated. If it is found that Mr. Shalan have obtained his
degree by fraud, the university will determine whether the
degree previously granted to him should be revoked.


Please note that we will not keep you updated in this matter
for the aforementioned reasons.


Thank you for taking the time to let us know your assertions
and kind regards,


Hokkaido University”

Now, Misawa’s fraudulent research with Shalan was funded by the Japan Society for the Promotion of Science (JSPS), and my reader contacted them, too. JSPS replied:

We are going to forward your e-mail to Hokkaido University.
Please note that we will not be able to answer your inquiries about your allegation as it will be handled by the regulations of University from now on.

This is how it works in Japan. Sometimes the only people entitled to investigate research fraud are the fraudsters themselves. As presumably is the case also at the Showa University – over to Aneurus Inconstans.


Oral oncology at Showa University

By Aneurus Inconstans

This story is from a country that doesn’t often appear in For Better Science reports, Japan. The institution involved is Showa University, a private comprehensive medical university with campuses spread in Tokyo, Yamanashi and Kanagawa Prefectures, that owns 8 hospitals and 1 clinic located throughout Tokyo and Yokohama. Hopefully medical practices on oral oncology at those hospitals do not rely much on what a bunch of researchers and medical doctors affiliated to the School of Dentistry published years ago in 15 papers (as of today) filled with questionable data. Most of the people involved are luckily all retired or no longer in academia, it seems. The major protagonists of this story are Masayasu Iwase and Masao Nagumo, but there are other recurring names.

One of the articles in question earned an expression of concern on September 29, 2021, from the International Journal of Cancer, owned by the Union for International Cancer Control (UICC) and published by Wiley. The article investigates whether anticancer drugs, like cisplatin (CDDP) and/or 5-fluorouracil (5-FU), can modulate Fas-mediated apoptosis in oral squamous cell carcinoma (SCC) cell lines NA and HSC-4. The editorial board acted swiftly and effectively in this case, they even spotted an additional problem themselves with Figure 1B. An expression of concern is a decent outcome, as the article is from 2003, and the authors claimed the raw data was no longer available, and they even denied any problem with Figure 5A and 5B.

Judge for yourself:

Iwase M*, Watanabe H, Kondo G, Ohashi M, Nagumo M. Enhanced susceptibility of oral squamous cell carcinoma cell lines to FAS-mediated apoptosis by cisplatin and 5-fluorouracil Int. J. Cancer (2003) doi: 10.1002/ijc.11239 (*corresponding author)

The expression of concern reads (highlight mine – A.):

“This Expression of Concern is for the above article, published online on May 30, 2003, in Wiley Online Library (wileyonlinelibrary.com), and has been published by agreement between the journal Editor-in-Chief, the first and corresponding author, Dr. Masayasu Iwase, and John Wiley & Sons, Ltd. The Expression of Concern has been agreed due to concerns regarding data presented in Figure 1, 5 and 6. In Figure 1B, in the right panel (HSC-4), bands #2-4 for FAS appear highly similar to bands #1-3 for GAPDH. In Figure 5A, bands for Procaspase-8 in “NA” appear similar to those for β-actin in “HSC-4″. In Figure 5B, bands for c-FLIP in “NA” and for c-FLIP in “HSC-4″ appear similar after brightness enhancement and vertical stretching. In Figure 6B, bands for β-actin in “NA” and” HSC-4″ appear similar after vertical stretching. The authors have been unable to provide original data underlying these images due to the time that has elapsed. The corresponding author does not agree to the above-mentioned issues in Figure 5A + B, but states that the mistakes in Figure 1B and Figure 6B occurred accidentally. He provided alternative images for correction of the issues in Figure 1B and Figure 6B, but due to the lack of original raw data, the origin of these images also remains uncertain. The author’s institution, Showa University, has been contacted but no investigation was initiated. As a result, the journal is issuing this Expression of Concern to alert readers.”

It seems that Showa University isn’t interested to understand what happened.

I guess we cannot rely much also on the publishers of the other papers by Iwase & Nagumo, although I have informed them, as we are mostly dealing with Elsevier and Spandidos Pubblications.

Lets start with Takaoka et al. 2007, published in that inglorious outlet called International Journal of Oncology. The article investigates the combined effects of anti-cancer drugs and epidermal growth factor (EGFR) receptor inibitors on the proliferation and induced apoptosis of SCC cells. Figure 4 and 5 contain a myriad of duplicated panels that are supposed to describe different proteins and conditions with different cell types. A multitude of blots were also reused in Uchida et al. 2007, published in the same journal, where oral SCC cells were treated with phosphatidylinositol 3-kinase inhibitors to evaluate their effects on apoptosis. The reused panels (boxes of same colors) have been sometimes squeezed vertically:

Takaoka S, Iwase M*, Uchida M, Yoshiba S, Kondo G, Watanabe H, Ohashi M, Nagumo M, Shintani S. Effect of combining epidermal growth factor receptor inhibitors and cisplatin on proliferation and apoptosis of oral squamous cell carcinoma cells Int. J. Oncol. (2007) doi: 10.3892/ijo.30.6.1469

Uchida M, Iwase M*, Takaoka S, Yoshiba S, Kondo G, Watanabe H, Ohashi M, Nagumo M, Shintani S. Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors Int. J. Oncol. (2007) doi: 10.3892/ijo.30.5.1163

To both threads in PubPeer, Dr. Iwase commented in February 2021 as following:

Dear Aneurus Inconstans, thank you for your series of valuable suggestions. We will sincerely verify the matters pointed out. I’m sorry, many collaborators have already resigned from academia. Therefore, we will report again after a while for verification.

The problematic Uchida et al. 2007 has its own issues in Figure 1 and 3:

In Figure 1 there’s one more duplication, a Western blot for the serine/threonine kinase Akt is also an actin control.

Figure 7 from Uchida et al. 2007 shares an actin control with another masterpiece, Kondo et al. 2006, published in Oral Oncology (by Elsevier), cell type and conditions were of course different again:

Kondo G, Iwase M*, Watanabe H, Uchida M, Takaoka S, Ohashi M, Nagumo M. Enhancement of susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells by phosphatidylinositol 3-kinase inhibitor Oral Oncol. (2006) doi: 10.1016/j.oraloncology.2005.11.015

Kondo et al. 2006 shares in turn a couple of Western blots with Iwase et al. 2003, the latter is the very first article I discussed above, yes, the one awarded with an expression of concern, and suddenly this story almost comes to full circle:

These evidences make me wonder whether also in Japan, likewise in China, medical doctors are pushed to publish research articles in international peer-reviewed journals (on top of their normal work with patients) for getting some sort of career advancement and salary rewards.

Lets move on to another paper, Iwase et al. 2006, published in International Immunopharmacology (by Elsevier), on the effects of cyclooxygenase-2 inhibitor on Fas-mediated apoptosis in neutrophils. Some bands look more similar than expected and splices are well recognizable. Then Cheshire, aka Actinopolyspora biskrensis, chimed in the treasure hunt and found even more:

Iwase M*, Takaoka S, Uchida M, Kondo G, Watanabe H, Ohashi M, Nagumo M. Accelerative effect of a selective cyclooxygenase-2 inhibitor on Fas-mediated apoptosis in human neutrophils Int. Immunopharmacol. (2006) doi: 10.1016/j.intimp.2005.08.017

Actinopolyspora biskrensis: “There may be additional issues in these two figures (cyan).”

Dr Iwase pleaded in this PubPeer thread, in February 2021, the following (highlight mine – A.):

Dear Dr. Aneurus Inconstans Thank you for the appropriate comments. I quit university 11 years ago and haven’t been doing any research since then. My colleagues Dr. Kondo, Dr. Takaoka and Dr. Uchida also retired from college more than 10 years ago. I have tried to visit the academia to verify and confirm the data against your comment. However, because of COVID-19, the government is requesting restrictions on movement and actions. I would be grateful if you could give me some time.

There’s a lot more to check, Dr Iwase. Yet another avalanche of utterly fake experiments in Iwase et al. 2008, the article supposedly shows the effect of EGFR inhibitors on phosphorylation of EGFR and Akt in HSC-2 cells (Figure 1), the effect of caspase-8 activation and Bid cleavage on Fas-mediated apoptosis in EGFR inhibitor-treated HSC-2 cells (Figure 4), and the effect of EGFR inhibitors on FADD, procaspase-8, and c-FLIP expression in HSC-2 cells (Figure 6). These three figures share several blots with three previous papers by the same group, such as the already discussed Uchida et al. 2007 and Takaoka et al. 2007, plus the new entry Iwase et al. 2007:

Iwase M*, Takaoka S, Uchida M, Yoshiba S, Kondo G, Watanabe H, Ohashi M, Nagumo M. Epidermal growth factor receptor inhibitors enhance susceptibility to Fas-mediated apoptosis in oral squamous cell carcinoma cells Oral Oncol. (2008) doi: 10.1016/j.oraloncology.2007.04.006

Iwase M*, Yoshiba S, Uchid M, Takaoka S, Kurihara Y, Ito D, Hatori M, Shintani S. Enhanced susceptibility to apoptosis of oral squamous cell carcinoma cells subjected to combined treatment with anticancer drugs and phosphatidylinositol 3-kinase inhibitors Int. J. Oncol. (2007) doi: 10.3892/ijo.31.5.1141

Then Yoshiba et al. 2011 published in Oncology Reports (yet another appalling Spandidos title), which is the most recent paper having Masayasu Iwase in the author list, but this time the corresponding author is Sayaka Yoshiba:

Yoshiba S*, Iwase M, Kurihara S, Uchida M, Kurihara Y, Watanabe H, Shintani S. Proteasome inhibitor sensitizes oral squamous cell carcinoma cells to TRAIL-mediated apoptosis Oncol. Rep. (2011) doi: 10.3892/or.2010.1127

Figure 4, same actin control (red boxes) shown for experiments with different cell types. Blue box indicate a potential mistake and it should read ++.

Again a comment by Dr. Iwase in PubPeer:

“Dear Dr. Aneurus Inconstans, thank you for your new comments. Dr. Yoshiba was unaware of your comment. I let her know about your comment. Only she works in academia. I urged her to respond to your comments promptly.

Dr. Yoshiba might be employed as assistant professor at Northern Yokohama Hospital accordingly to her latest article listed in PubMed, but she has never replied as of today. We just hope her corresponding authorship in that paper doesn’t imply a handover of Iwase’s research to her.

Unlike Iwase, Masao Nagumo is never the corresponding author, however, he is almost always listed as last name, and can boast 10 flagged papers in PubPeer making him the record-holder among these doctors. Was he a sort of “grey eminence” behind the scenes at the Department of Oral and Maxillofacial Surgery at Showa University? We can only speculate, but four other problematic papers again include Nagumo as last name. Both Kinugasa et al. 2005 and Imoto et al. 2006 have a problem with RT-PCR GAPDH controls:

Imoto E*, Kakuta S, Hori M, Yagami K, Nagumo M. Adhesion of a chondrocytic cell line (USAC) to fibronectin and its regulation by proteoglycan. J. Oral Pathol. Med. (2002) doi: 10.1046/j.0904-2512.2001.00202.x

Even more serious are Uyama et al. 2004 and Yagami et al. 2004:

Uyama Y*, Yagami K, Hatori M, Kakuta S, Nagumo M. Recombinant human bone morphogenetic protein-2 promotes Indian hedgehog-mediated osteo-chondrogenic differentiation of a human chondrocytic cell line in vivo and in vitro Differentiation (2004) doi: 10.1111/j.1432-0436.2004.07201001.x

Figure 3, twenty-three bands appear more than once (boxes of same color) and the whole figure is a complete patchwork. This is better appreciated by looking at the enhanced contrast version of the figure, where many splices are visible too.

Yagami K*, Uyama Y, Yoshizawa Y, Kakuta S, Yamaguchi A, Nagumo M. A human chondrogenic cell line retains multi-potency that differentiates into osteoblasts and adipocytes Bone (2004) doi: 10.1016/j.bone.2003.12.016

Figure 3, some bands have been cropped, flipped and pasted into panels to describe mRNA expression of different genes (boxes of same color). GAPDH controls also look strange. It seems that the corresponding author Kimitoshi Yagami is now professor at Matsumoto Dental University, a private university located in the city of Shiojiri, in Nagano Prefecture.

A special mention goes to Satoru Shintani, coauthor with Iwase and Nagumo of 4 articles discussed above, currently CEO at an oral and maxillofacial surgery clinic in Tokyo and out of academia since 2014, who can boast 7 papers in total on PubPeer as of today. During his later academic work Dr. Shintani had also lots of fun with Traditional Chinese Medicine (TCM) performed in collaboration with Chinese colleagues. The following studies tell us about the anti-cancer properties of Peonia moutan on carcinoma cells and the anti-osteoporotic effects of herbal extracts on bone cells in vitro. One of these papers was published in legendary BMC Complementary and Alternative Medicine by Springer, a title which is an ethics statement in itself:

Actinopolyspora biskrensis:
Figure 2 appears to have a repeated image.

Li C, Yazawa K, Kondo S*, Mukudai Y, Sato D, Kurihara Y, Kamatani T, Shintani S. The root bark of Paeonia moutan is a potential anticancer agent in human oral squamous cell carcinoma cells Anticancer Res. (2012) PMID: 22753719

Actinopolyspora biskrensis:
Figure 2 appears to have a repeated image.
Actinopolyspora biskrensis: “Figure 9A appears to have a repeated image. There are others which have similarities, however I believe this is due to dirty equipment.

Mukudai Y*, Kondo S, Koyama T, Li C, Banka S, Kogure A, Yazawa K, Shintani S. Potential anti-osteoporotic effects of herbal extracts on osteoclasts, osteoblasts and chondrocytes in vitro BMC Complement Altern Med. (2014) doi: 10.1186/1472-6882-14-29

And finally this one, Mukudai et al. 2016, published in a Hindawi journal, whose name also says it all, Evidence Based Complementary and Alternative Medicine. An intrepid soul might consider to systematically check out the papers in this journal one day, it could be fun.

Mukudai Y*, Zhang M, Shiogama S, Kondo S, Ito C, Motohashi H, Kato K, Fujii M, Shintani S, Shigemori H, Yazawa K, Shirota T. Methanol and Butanol Extracts of Paeonia lutea Leaves Repress Metastasis of Squamous Cell Carcinoma Evid Based Complement Alternat Med (2016) doi: 10.1155/2016/6087213

Let’s just hope the scientific integrity of these doctors does not reflect the quality of their work as medical practitioners with patients…

Original image: Showa University

P.S

Слава Україні! Героям слава!


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5 comments on “Oral oncology at Showa University

  1. Smut Clyde

    “The root bark of Paeonia moutan is a potential anticancer agent in human oral squamous cell carcinoma cells Anticancer Res. (2012) PMID: 22753719″

    No remarks about “Anticancer Research”, a journal known for its “negotiable peer review standards”? Published by the Delinasios family (which is to say, the International Institute of Anticancer Research) in the time they can spare from organising predatory conferences? I am disappointed.

    Previously encountered in the context of Wen Jiang and Cardiff University.

    Like

  2. Good news:

    the Editor-in-Chief of the journal “Bone” informed me that the paper Yagami_et_al_2004 is in the process of being retracted.

    Like

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