“Morty“ is a cancer researcher and a pseudonymous data integrity sleuth, a member of our papermill-hunting team. Recently, Morty read a review, allegedly relevant to his own work. He had a closer look at the references, and half of them are no good at all, mostly Chinese papermills published in trash journals.

Below is Morty’s analysis, I provided some editing to his draft.

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Cancer and anesthesia – a question of trust

By “Morty”

In the beginning of 2020, we started to identify fabricated papers produced by the Chinese papermills. Fraudsters based in China, Russia and the Middle East continue to infiltrate scholarly literature with their fabricated articles. The next generation papermills are even more professional and usually avoid sloppy mistakes, like duplication of Western immunoblots or micrographs. A crisis of trust in scientific literature is being discussed for years already.

The problem certainly did not begin with papermills. Difficulties with reproducing published results have been discussed for a long time. A decade has passed since Bayer and Amgen published their devastating conclusion from their attempts to reproduce cancer related studies. Scientists from Bayer could only reproduce 25% of 67 papers published in well recognized journals (Prinz, F et al., 2011). One year later, Amgen scientist followed up with a study showing that only 11% of 53 landmark papers were reproducible (Begley CG and Ellis LM, 2012). 

The crisis of trust has only increased in scope since Bayer and Amgen presented their concerns, and with the expansion of the pay-to-publish Open Access, we are now witnessing an explosion of misinformation and nonsensical content in published literature. The problem is that the actors who could contribute to improvements show little progress in doing so. I have been in contact with publishers, research institutions, granting authorities, patient organization, and the US National Library of Medicine. The general impression is that there is no interest in introducing changes and regulations in order to improve the quality and trust in scientific literature. This is surprising and sad, when you consider the long-term consequences of misinformation in scientific literature.   

The outlook is grim. Asian papermills continue to infiltrate scholarly literature with their fabricated articles. Their fraudulent papers are usually highly cited, because also citations are being bought and sold. That is part of their business model. The papermillers collaborate with rogue editors to make their favourite journals more attractive for future customers. It gives the readers a false impression that these fake papers have merit. Furthermore, the irresponsible journals which distribute the misinformation are rewarded with high impact factors. 

Three years after our first identification of the Chinese paper mill papers, and thousands of fake papers reported, we are wondering how the scientific community will face the flood of misinformation. Many fabricated papers were related to cancer, and they present false promising results, arguing for further clinical studies. 

How are these articles perceived in the research community? Are they really read by other scientists and are they really cited outside the papermill citation-market milieu? To answer these questions, I picked a typical review article covering a generally important subject affecting a large number of patients all over the World: How does the choice of anaesthesia affect cancer?

The review article was written by a research group affiliated to university hospitals in Belgium. In the heart of Europe, without any obvious connection to Asian papermills:

The corresponding author, Professor Ramses Forsyth is Chair of Department of Pathology & Experimental Pathology at the Vrije Universiteit Brussel. The penultimate author Dr Caroline Vanpeteghem is deputy head for anaesthesiology at the University Hospital Ghent. The academic editor handling this review for almost 4 months was Wolfgang Liedtke, former Duke University professor and now Global Development Chair at Regeneron. We have no reason to question their expertise and competence.

Admittedly, this review article is published in the journal Cancers, run by MDPI, a publisher with a fringe reputation. Nevertheless, such review articles are still used by researchers, even if by those who just looking for a quick reference for their own manuscript. 

The reference list is as long as it is depressing. The authors have listed as many as 165 citations, and they evidently put aside all critical sense when organizing these references. It’s a mess of misinformation and poor research assembled to make a story. A story to mislead. An echo from the paper mills in China.

From the 165 references, I left out 17 (review articles and articles published before 2000) and ended up with 148 references. These cited original studies were analysed for quality of data in general, content of data duplications (manual screening plus ImageTwin analysis), while checking for any concerns reported at PubPeer. A PubPeer report was published for those references which contained data duplications or other issues of highly questionable data. 

From the 148 references of original articles, I categorized 68 references (46 %) as questionable. The criteria for being categorized as questionable, were lack of solid data in order to support the conclusion and the authors’ argument for further clinical studies, or cases of data duplication/falsification or fabrication of data. Most of the references in this category were published in journals which we earlier categorized as problematic. They have been infiltrated by paper mills, uncritically publishing a large number of fabricated papers. Furthermore, they act slowly when fabricated papers are reported. 

Examples of journals in the category:

• European Review for Medical and Pharmacological Sciences
• Brazilian Journal of Medical and Biological Research
• Biomedicine & Pharmacotherapy
• Molecular Medicine Reports
• Journal of Cellular Biochemistry
• Anticancer Research
• Bioengineered
• Life Sciences
• Oncotarget
• Cell Cycle

An overview of the analysis is found here:

Furthermore, 43 of the references were so seriously flawed that publishing an expression of concern in PubPeer was warranted. Here are some examples:

Reference 10, falsification of micrographs:

M Xia , N-N Ji , M-L Duan , J-H Tong , J-G Xu , Y-M Zhang , S-H Wang Dexmedetomidine regulate the malignancy of breast cancer cells by activating α2-adrenoceptor/ERK signaling pathway European Review for Medical and Pharmacological Sciences (2016) Vol. 20.16 (3500-3506)

Reference 22, falsification of micrographs:

Xiao Yang , Yao-tun Zheng , Wei Rong Sevoflurane induces apoptosis and inhibits the growth and motility of colon cancer in vitro and in vivo via inactivating Ras/Raf/MEK/ERK signaling Life Sciences (2019) doi: 10.1016/j.lfs.2019.116916 

In this paper there were no acknowledgements, and the study was not funded. This is typical for papermill papers and should be a red flag for peer-reviewers and publishers, it they care.Reference 24, similar situation:

S. Q. Sun , L. J. Ren , J. Liu , P. Wang , S. M. Shan Sevoflurane inhibits migration and invasion of colorectal cancer cells by regulating microRNA-34a/ADAM10 axis Neoplasma (2019) doi: 10.4149/neo_2018_181213n962 

Reference 25, a variant of the many different questionable Western immunoblots:

Lihua Fan , Yini Wu , Jianping Wang , Jiaqun He , Xin Han Sevoflurane inhibits the migration and invasion of colorectal cancer cells through regulating ERK/MMP-9 pathway by up-regulating miR-203 European Journal of Pharmacology (2019) doi: 10.1016/j.ejphar.2019.01.025

Reference 42, duplication of microscopy data and questionable Western immunoblots:

Chao Meng , Linlin Song , Juan Wang , Di Li , Yanhong Liu , Xiaoguang Cui Propofol induces proliferation partially via downregulation of p53 protein and promotes migration via activation of the Nrf2 pathway in human breast cancer cell line MDA-MB-231 Oncology Reports (2017) doi: 10.3892/or.2016.5332

In this case, the authors replied to the PubPeer post, which is unusual.

“For the pictures inside the red and blue boxes, we didn’t find any traces of duplicate use. For the pictures inside the green box, it does have repeatability suspicion. However, these pictures all in the NC and VC groups which were treated with nothing and vehicle-control respectively. This will not affect to lead to a true and reproducible test result. In order to avoid the effects of images on outcomes, we decided to repeat the experiments in NC and VC groups and to upload the relevant images.“

The red and blue boxes show however the same image. And there was also this:

Reference 43, in the same journal:

Nengli Yang , Yafeng Liang , Pei Yang , Fuhai Ji Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer Oncology Reports (2017) doi: 10.3892/or.2017.5514 

Reference 50, obvious data re-use:

Yufeng Miao , Youwei Zhang , Haijun Wan , Longbang Chen , Fangyu Wang GABA-receptor agonist, propofol inhibits invasion of colon carcinoma cells Biomedicine & Pharmacotherapy (2010) doi: 10.1016/j.biopha.2010.03.006

Reference 56, an utter mess:

Ting Gong , Xue Ning , Zhiya Deng , Mingyu Liu , Beixian Zhou , Xijun Chen , Shisi Huang , Yan Xu , Zhongqing Chen , Rongcheng Luo Propofol‐induced miR‐219‐5p inhibits growth and invasion of hepatocellular carcinoma through suppression of GPC3‐mediated Wnt/β‐catenin signalling activation Journal of Cellular Biochemistry (2019) doi: 10.1002/jcb.28952 

Reference 59, in a BMC journal catering to China:

Yi-Ping Liu , Jin-Yu Heng , Xin-Yu Zhao , En-You Li The inhibition of circular RNA circNOLC1 by propofol/STAT3 attenuates breast cancer stem cells function via miR-365a-3p/STAT3 signaling Journal of Translational Medicine (2021) doi: 10.1186/s12967-021-03133-5 

Reference 112, in Scientific Reports:

Wei Xuan , Hailin Zhao , James Hankin , Lin Chen , Shanglong Yao , Daqing Ma Local anesthetic bupivacaine induced ovarian and prostate cancer apoptotic cell death and underlying mechanisms in vitro Scientific Reports (2016) doi: 10.1038/srep26277

Some of the problematic issues were also published in more respectable journals, like British Journal of Cancer (reference 19):

H Huang , L L Benzonana , H Zhao , H R Watts , N J S Perry , C Bevan , R Brown , D Ma Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination British Journal of Cancer (2014) doi: 10.1038/bjc.2014.426

Reference 29, from a journal published by the American Society of Anesthesiologists:

Wenwen Zhang , Bo Sheng , Sisi Chen , Hailin Zhao , Lingzhi Wu , Yibing Sun , Jiang Cui , Xueqiong Zhu , Daqing Ma Sevoflurane Enhances Proliferation, Metastatic Potential of Cervical Cancer Cells via the Histone Deacetylase 6 Modulation In Vitro Anesthesiology (2020) doi: 10.1097/aln.0000000000003129 

Reference 66, another respectable anaesthesia society journal:

Xiaoyu Zheng , Linlin Dong , Su Zhao , Quanyi Li , Dandan Liu , Xidong Zhu , Xiaona Ge , Ruzhe Li , Guonian Wang Propofol Affects Non-Small-Cell Lung Cancer Cell Biology By Regulating the miR-21/PTEN/AKT Pathway In Vitro and In Vivo Anesthesia & Analgesia (2020) doi: 10.1213/ane.0000000000004778

The last author assured on PubPeer:

“This error does not affect the results, discussion, or conclusions. The authors sincerely apologize to the editors and readers for any inconvenience or confusion. We declare that all the data are authentic and reliable and all experiments are done by ourselves.“

A reason to be even more concerned, is the fact that 16 of the 148 references (~11%) already had a concern reported in PubPeer. Here we are talking about serious fabrication and falsification of data.Let me show you some examples: Reference 48, falsified data from the notorious Brazilian J Medical and Biological Research:

X. Huang , Y. Teng , H. Yang , J. Ma Propofol inhibits invasion and growth of ovarian cancer cells via regulating miR-9/NF-κB signal Brazilian Journal of Medical and Biological Research (2016) doi: 10.1590/1414-431×20165717 

References 52, 46 and 82, duplication of data and reuse from other publications:

• • JINQUAN XU , WEIYUN XU , JIAQUN ZHU Propofol suppresses proliferation and invasion of glioma cells by upregulating microRNA-218 expression Molecular Medicine Reports (2015) doi: 10.3892/mmr.2015.4014 
• • Zhang Ye , Li Jingzhong , Liu Yangbo , Chen Lei , Yuan Jiandong Propofol Inhibits Proliferation and Invasion of Osteosarcoma Cells by Regulation of MicroRNA-143 Expression Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics (2014) doi: 10.3727/096504014×13890370410203 
• • Z.T. Wang , H.Y. Gong , F. Zheng , D.J. Liu , T.L. Dong Propofol suppresses proliferation and invasion of pancreatic cancer cells by upregulating microRNA-133a expression Genetics and Molecular Research (2015) doi: 10.4238/2015.july.3.28 

Reference 53, duplication of data in Medical Science Monitor:

Fenghua Liu , Fengyu Qiu , Min Fu , Huayong Chen , Hui Wang Propofol Reduces Epithelial to Mesenchymal Transition, Invasion and Migration of Gastric Cancer Cells through the MicroRNA-195-5p/Snail Axis Medical Science Monitor (2020) doi: 10.12659/msm.920981

Reference 67, a classic! Nonsensical content, Bioengineered:

Hongwei Wang, Hongmei Jiao, Ziru Jiang , Renyi Chen Propofol inhibits migration and induces apoptosis of pancreatic cancer PANC-1 cells through miR-34a-mediated E-cadherin and LOC285194 signals Bioengineered (2020) doi: 10.1080/21655979.2020.1754038 

Also, Actinopolyspora biskrensis noted that “the corresponding author‘s email address bears no resemblance to their name.” In February 2021, the author Renyi Chen announced:

“Let’s withdraw this article. Thanks. The Journal must know about this problem . We can no longer use this article.“

Nothing happened since. The pika remains as Figure 3. Reference 68, a typical type 1 papermill product, BMC Cancer:

Hai Sun , Dengyu Gao Propofol suppresses growth, migration and invasion of A549 cells by down-regulation of miR-372 BMC Cancer (2018) doi: 10.1186/s12885-018-5175-y 

Reference 121, from Artifical Cells Nanomedicine and Biotechnology, one of the favourites among the papermills:

Hai Sun , Yan Sun Lidocaine inhibits proliferation and metastasis of lung cancer cell via regulation of miR-539/EGFR axis Artificial Cells Nanomedicine and Biotechnology (2019) doi: 10.1080/21691401.2019.1636807

In this case, an Expression of Concern was issued in January 2021:

“After publication of this article, questions about the scientific integrity of the article content were brought to the Publisher and Editor’s attention. We reached out to the authors requesting that they supply information that would confirm the article’s integrity. The authors provided several files in response to our queries, but they were unable to provide the original data in a format which satisfies our requirements to confirm the authenticity of some types of data, including the western blots. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution.”

Reference 134 goes to a Cell paper with a PubPeer history:

Hua Gao, Goutam Chakraborty , Ai Ping Lee-Lim , Qianxing Mo , Markus Decker , Alin Vonica , Ronglai Shen , Edi Brogi , Ali H. Brivanlou, Filippo G. Giancotti The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites Cell (2012) doi: 10.1016/j.cell.2012.06.035

Reference 141 goes to a paper by the MD Anderson researcher Anil K Sood, his name is a huge red flag:

Sood, A.K.; Bhatty, R.; Kamat, A.A.; Landen, C.N.; Han, L.; Thaker, P.H.; Li, Y.; Gershenson, D.M.; Lutgendorf, S.; Cole, S.W. Stress Hormone–Mediated Invasion of Ovarian Cancer Cells. Clin. Cancer Res. 2006, DOI: 10.1158/1078-0432.CCR-05-1698

The conclusion from this study is that the fabricated papers from the Chinese paper mills are continuing to infiltrate the scholarly literature. Misinformation is spread to review articles by research groups at well-respected research institutions in Europe. In this case we are talking about clinical information. We risk that future clinical studies will be based on incorrect information, which will threaten the patient safety. We need more quality control in scientific publishing and a more strict regulation of this business. Today, we are in a situation where public funds finance a very destructive spread of scientific misinformation, which we must stop.  

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