The practice of clinical research is strictly regulated by law. During submission and review processes, compliance of such research with the laws enforced in the country where it was conducted is not always correctly filled in by the authors or verified by the editors. Here, we report a case of a single institution for which one may find hundreds of publications with seemingly relevant ethical concerns, along with 10 months of follow-up through contacts with the editors of these articles. We thus argue for a stricter control of ethical authorization by scientific editors and we call on publishers to cooperate to this end. We present an investigation of the ethics and legal aspects of 456 studies published by the IHU-MI (Institut Hospitalo-Universitaire Méditerranée Infection) in Marseille, France. We identified a wide range of issues with the stated research authorization and ethics of the published studies with respect to the Institutional Review Board and the approval presented. Among the studies investigated, 248 were conducted with the same ethics approval number, even though the subjects, samples, and countries of investigation were different. Thirty-nine (39) did not even contain a reference to the ethics approval number while they present research on human beings. We thus contacted the journals that published these articles and provide their responses to our concerns. It should be noted that, since our investigation and reporting to journals, PLOS has issued expressions of concerns for several publications we analyze here. This case presents an investigation of the veracity of ethical approval, and more than 10 months of follow-up by independent researchers. We call for stricter control and cooperation in handling of these cases, including editorial requirement to upload ethical approval documents, guidelines from COPE to address such ethical concerns, and transparent editorial policies and timelines to answer such concerns. All supplementary materials are available.

We, as scientists, doctors, or concerned citizens, demand the establishment of an independent scientific inquiry commission to evaluate these breaches and determine the necessary actions. At a minimum, we hope that those responsible for these serious ethical, scientific, and managerial failings will be removed from teaching, leadership, and supervisory roles to prevent the spread of these harmful research practices to young researchers and other research teams. The reputation of French research has already suffered significant damage due to these deviant practices and their tragic consequences. This global scandal, passively observed by supervisory bodies, governments, and the administration of Aix-Marseille University, has directly and indirectly cost many human lives. It is intolerable that empty statements and half-measures continue to prevail. The time has come for strong, exemplary, and coherent actions that meet societal expectations and address the stakes at hand. The French scientific community, supported by a truly independent commission, must take responsibility and determine the appropriate sanctions for these grave breaches, which sometimes border on criminal conduct.

Concomitant inhibition of PI3Kβ, IGF1R and MAPK signaling are leading to full long-term pathway blockade. A) +B) Effects of treatment with the indicated inhibitors as single-agents or in combination on WM-266-4 (A) or RVH-421 (B) were evaluated by immunoblotting using phospho-specific or total target protein antibodies. PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, IGF1Ri (A)=AEW541, IGF1Ri (B)=Figitumumab-like antibody, MEKi=MEK162

Recently, an article by Seneff et al. entitled “Innate immunosuppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs” was published in Food and Chemical Toxicology (FCT). Here, we describe why this article, which contains unsubstantiated claims and misunderstandings such as “billions of lives are potentially at risk” with COVID-19 mRNA vaccines, is problematic and should be retracted. We report here our request to the editor of FCT to have our rebuttal published, unfortunately rejected after three rounds of reviewing. Fighting the spread of false information requires enormous effort while receiving little or no credit for this necessary work, which often even ends up being threatened. This need for more scientific integrity is at the heart of our advocacy, and we call for large support, especially from editors and publishers, to fight more effectively against deadly disinformation.

Supplementary Figure Legends, Table Legends

Evaluation of the in vitro synergy in anti-proliferation and the MAPK pathway suppression of MEK and SHP2, PI3K, or RTK inhibitors.

Evaluation of the in vivo combination benefit and the MAPK pathway suppression of MEK and SHP2 inhibitors in MIA PaCa-2 xenograft and a colon cancer PDX model.

A list of KRAS mutant cell lines in the study with lineages, zygosity determined by RNAseq, and percentages of p-MEK reduction by 5 micromolar SHP099 in the MEKi combination group.

Supplementary Figure S1. Comparison of drop out phenotypes in MKN45, RKO, HT1080 highlighting selected pan-lethal genes. Supplementary Figure S2. The genes that scored as lethal by both RNAi and CRISPR were strongly enriched for known essential genes classes. Supplementary Figure S3. To identify likely off-target hits the lethality scores of non-expressed genes were examined, as they are expected not to be required for cell viability. Supplementary Figure S4. shRNAs directed towards CDK9 do not show robust protein depletion. Supplementary Figure S5. Additional methods measuring the proliferation effects of individual sgRNA/shRNAs to validate the impact that targeting selected genetic dependencies have on cell viability. Supplementary Figure S6. Correlation analysis displaying features that correlated most significantly with sgRNA potency. Supplementary Figure S7. Effect of relative position within a gene on sgRNA viability effects. Supplementary Figure S8. Non-scoring sgRNA in conserved Pfam domains have a reduced editing efficiency compared to guides with strong viability effects. Supplementary Figure S9. Multiple genomic cuts result in DNA damage induced G2/M cell cycle arrest. Supplementary Figure S10. Multiple genomic cuts lead to an increase in cell death. Supplementary Figure S11. Pie chart demonstrating that the overall contribution of copy number effects in determining essential genes in aneuploid lines is relatively minor.

PI3K pathway inhibition using PI3Kβi/PI3Kαi or PI3Kβi/IGF1Ri enhances the anti-proliferative effect of the BRAF/MEK inhibition regimen in PTENLOF/BRAFMUT cell lines and shifts the response towards cell death A+B) Validation of BRAFi/MEKi activity in RVH-421 (A) and WM-266-4 (B) in the absence or presence of PI3Kβi/PI3Kαi or PI3Kβi/IGF1Ri using proliferation (upper panels; growth matrix highlighting percentages of proliferation inhibition relative to DMSO) or cell death assays (lower panels; fraction of PI-positive, dead cells). PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, IGF1Ri=AEW541, BRAFi=LGX818, MEKi=MEK162

PI3Kβi (rac-KIN-193) treatment induces the interaction of p85 with a panel of proteins in PTENLOF/BRAFMUT melanoma. RVH-421 were treated with DMSO or 1μM PI3Kβi for 2h. Lysates were subjected to immunoprecipitation using an antibody targeting p85. Proteins in the range of 75 to 250 kDa were identified by LC-MS as described. Total spectra counts were used as a measure for protein quantity. The table summarizes the proteins enriched upon PI3Kβi treatment in the p85 precipitate. A spectral count ratio of 4 (log2 (PI3Kβi /DMSO) > 2) was taken as an arbitrary cutoff for significant enrichment.

IGF1R inhibition synergizes with PI3Kβ inhibition in WM-266-4, but not in A-375. A) Synergistic proliferation inhibition upon PI3K/IGF1R inhibitor combination in WM-266-4 cells. WM-266-4 cells were treated with increasing concentrations of PI3Ki and IGF1Ri as single-agents or in combination with a fixed concentration of 1.1μM IGF1Ri. The data shown represents the mean ({plus minus}SEM) of two replicates. B) + C) Determination of PI3K/IGF1R inhibitor synergy in WM-266-4 (B) and A-375 (C) using proliferation assays. Dose matrices highlight percentages of proliferation inhibition relative to DMSO with 100 indicating complete block of proliferation and >100 indicative of cell death. SS, synergy score. PI3Kβi1/2=rac-KIN-193/GSK-2636771, panPI3Ki=GDC0941, PI3Kαi=BYL719, IGF1Ri=AEW541

Correlation analysis matrix displaying features that correlate most strongly with sgRNA's having off target effects.

Changes in phospho-SHP2 levels following MEKi treatment in studied KRAS mutant lines.

The practice of clinical research is strictly regulated by law. During submission and review processes, compliance of such research with the laws enforced in the country where it was conducted is not always correctly filled in by the authors or verified by the editors. Here we review 456 studies published by the IHU Méditerranée Infection (Marseille, France) and identify a range of issues with the stated authorization of the research, ethically and potentially legally. Of these, 248 were conducted with the same ethics committee reference, even though the subjects, samples and countries were different. Thirty-nine did not even contain a reference to the ethics committee while they contain research on human beings. With this example, we call for stricter control by publishers of the regulatory documentation related to clinical research during the publication process. All supplementary materials are available on https://osf.io/ueqf8/.

Annotations for the sgRNA libraries containing sequences, target gene information, Zscore and RNAseq data for each cell line screened.

Annotations for the sgRNA/shRNA libraries containing average Zscore and copy number information.

Despite major dependence of PTENLOF/BRAFMUT melanoma cell lines on PI3Kβ, PI3Kαi synergizes with PI3Kβi to inhibit downstream signaling upon long-term treatment. A) +B) Effects of treatment with the indicated inhibitors as single-agents or in combination for 2h (A) and 72h (B) on PI3K signaling was determined by immunoblotting in PTENLOF/BRAFMUT melanoma cell lines. PI3Kβi=rac-KIN-193, PI3Kαi=BYL719, PI3Kδi=CAL101