RETRACTED: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.
Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the effect of hydroxychloroquine on respiratory viral loads.
French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point.
Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported in the litterature for untreated patients. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.
Despite its small sample size, our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). Concerns have been raised regarding this article, the substance of which relate to the articles' adherence to Elsevier's publishing ethics policies and the appropriate conduct of research involving human participants, as well as concerns raised by three of the authors themselves regarding the article's methodology and conclusions. Elsevier's Research Integrity and Publishing Ethics Team, in collaboration with the journal's co-owner, the International Society of Antimicrobial Chemotherapy (ISAC), and with guidance from an impartial field expert acting in the role of an independent Publishing Ethics Advisor, Dr. Jim Gray, Consultant Microbiologist at the Birmingham Children's and Women's Hospitals, U.K., conducted an investigation and determined that the below points constituted cause for retraction: • The journal has been unable to confirm whether any of the patients for this study were accrued before ethical approval had been obtained. The ethical approval dates for this article are stated as being 5th and 6th of March 2020 (ANSM and CPP respectively), while the article states that recruitment began in “early March”. The 17th author, Prof. Philippe Brouqui, has confirmed that the start date for patient accrual was 6th March 2020. The journal has not been able to establish whether all patients could have entered into the study in time for the data to have been analysed and included in the manuscript prior to its submission on the 20th March 2020, nor whether all patients were enrolled in the study upon admission as opposed to having been hospitalised for some time before starting the treatment described in the article. Additionally, the journal has not been able to establish whether there was equipoise between the study patients and the control patients. • The journal has not been able to establish whether the subjects in this study should have provided informed consent to receive azithromycin as part of the study. The journal has concluded that that there is reasonable cause to conclude that azithromycin was not considered standard care at the time of the study. The 17th author, Prof. Philippe Brouqui has attested that azithromycin treatment was not, at the time of the study, an experimental treatment but a possible treatment for, or preventative measure against, bacterial superinfections of viral pneumonia as described in section 2.4 of the article, and as such the treatment should be categorised as standard care that would not require informed consent. This does not fully address the journal's concerns around the use of azithromycin in the study. In section 3.1 of the article, it is stated that six patients received azithromycin to prevent (rather than treat) bacterial superinfection. All of these were amongst the patients who also received hydroxychloroquine (HCQ). None of the control patients are reported to have received azithromycin. This would indicate that only patients in the HCQ arm received azithromycin, all of whom were in one center. The recommendations for use of macrolides in France at the time the study was conducted indicate that azithromycin would not have been a logical agent to use as first-line prophylaxis against pneumonia due to the frequency of macrolide resistance amongst bacteria such as pneumococci. These two points suggest that azithromycin would not have been standard practice across southern France at the time the study was conducted and would have required informed consent. • Three of the authors of this article, Dr. Johan Courjon, Prof. Valérie Giordanengo, and Dr. Stéphane Honoré have contacted the journal to assert their opinion that they have concerns regarding the presentation and interpretation of results in this article and have stated they no longer wish to see their names associated with the article. • Author Prof. Valérie Giordanengo informed the journal that while the PCR tests administered in Nice were interpreted according to the recommendations of the national reference center, it is believed that those carried out in Marseille were not conducted using the same technique or not interpreted according to the same recommendations, which in her opinion would have resulted in a bias in the analysis of the data. This raises concerns as to whether the study was partially conducted counter to national guidelines at that time. The 17th author, Prof. Philippe Brouqui has attested that the PCR methodology was explained in reference 17 of the article. However, the article referred to by reference 17 describes several diagnostic approaches that were used (one PCR targeting the envelope protein only; another targeting the spike protein; and three commercially produced systems by QuantiNova, Biofire, and FTD). This reference does not clarify how the results were interpreted. It has also been noted during investigation of these concerns that only 76% (19/25) of patients were viral culture positive, resulting in uncertainty in the interpretation of PCR reports as has been raised by Prof. Giordanengo. As part of the investigation, the corresponding author was contacted and asked to provide an explanation for the above concerns. No response has been received within the deadline provided by the journal. Responses were received by the 3rd and 17th authors, Prof. Philippe Parola and Prof. Philippe Brouqui, respectively, and were reviewed as part of the investigation. These two authors, in addition to 1st author Dr. Philippe Gautret, 13th author Prof. Philippe Colson, and 15th author Prof. Bernard La Scola, disagreed with the retraction and dispute the grounds for it. Having followed due process and concluded the aforementioned investigation and based on the recommendation of Dr. Jim Gray acting in his capacity as independent Publishing Ethics Advisor, the co-owners of the journal (Elsevier and ISAC) have therefore taken the decision to retract the article.
Gautret P
，Lagier JC
，Parola P
，Hoang VT
，Meddeb L
，Mailhe M
，Doudier B
，Courjon J
，Giordanengo V
，Vieira VE
，Tissot Dupont H
，Honoré S
，Colson P
，Chabrière E
，La Scola B
，Rolain JM
，Brouqui P
，Raoult D
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Gremlin-2 is a novel tumor suppressor that negatively regulates ID1 in breast cancer.
Breast cancer is one of the most common cancers in women and is closely associated with obesity. Gremlin-2 (GREM2), an antagonist for bone morphogenetic proteins (BMPs), has been considered an inhibitor of adipogenic differentiation in adipose-derived stromal/stem cells. However, the role of GREM2 in breast cancer cells remains largely unknown, and its signaling mechanism has yet to be clarified.
Bioinformatics analysis was conducted using public databases. Breast cancer cells overexpressing mock or GREM2 were used for in vitro and in vivo studies. Cell viability, colony formation, migration, and animal studies were performed to investigate the role of GREM2 in breast cancer cells. Screening of target genes affected by GREM2 overexpression in breast cancer cells was performed through RNA sequencing (RNA-seq) analysis.
The expression level of GREM2 mRNA was significantly reduced in both breast cancer tissues and cell lines. Kaplan-Meier analysis showed that low expression of GREM2 and high methylation of the GREM2 promoter were each associated with poor patient survival. The low mRNA expression of GREM2 in breast cancer cells was increased by the demethylating agent decitabine. Breast cancer cells overexpressing GREM2 decreased cell proliferation when compared to control cells, both in vitro and in vivo. Through comparison of RNA-seq analysis between cell lines and tissue samples, gene ontologies that were consistently upregulated or downregulated by GREM2 in breast cancer were identified. In particular, the expression of inhibitor of DNA-binding-1 (ID1) was repressed by GREM2. BMP2 is one of the upstream regulators that increases the expression of ID1, and the expression of ID1 reduced by GREM2 was restored by overexpression of BMP2. Also, the migration ability of breast cancer cells, which had been suppressed by GREM2, was restored by BMP2 or ID1.
Low expression of GREM2 in breast cancer cells is associated with hypermethylation of the GREM2 promoter, which may ultimately contribute to poor patient survival. GREM2 participates in regulating the expression of various genes, including ID1, and is involved in suppressing the proliferation of breast cancer cells. This suggests that GREM2 has the potential to act as a novel tumor suppressor in breast cancer.
Jung J
，Kim NH
，Park J
，Lim D
，Kwon M
，Gil W
，Jung S
，Go M
，Kim C
，Cheong YH
，Lee MH
，Park HS
，Eom YB
，Park SA
... -
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miR-379-5p affects breast cancer cell behavior by targeting UBE2E3 ubiquitin conjugating enzyme.
MicroRNAs (miRNAs) play an increasingly recognized role in modulating cancer development. Due to their function in regulating gene expression, miRNAs can suppress or promote tumorigenesis. miR-379-5p expression is downregulated in multiple human cancers, including breast and bladder cancers. However, the mRNAs targeted by miR-379-5p that promote cancer development have not been fully identified. Our goal was to identify a gene whose expression is regulated by miR-379-5p, and which may contribute to cancer development in cells where miR-379-5p expression is reduced. Bioinformatics analysis showed the UBE2E3 ubiquitin conjugating enzyme gene to be a potential target for miR-379-5p. To verify that UBE2E3 is a target, we transfected normal human epithelial mammary cells and breast adenocarcinoma cell lines with a miR-379-5p mimic. The mimic reduced UBE2E3 mRNA and protein levels, as would be predicted for a miR-379-5p target. To determine if UBE2E3 is a direct target of miR-379-5p, we engineered two luciferase reporter gene constructs to contain either a wild-type putative miR-379-5p binding sequence isolated from the 3'UTR of the UBE2E3 gene, or a scrambled sequence. The luciferase assay showed that the miR-379-5p mimic suppressed luciferase activity for the WT binding sequence reporter, but not for the scrambled reporter, showing that the effect of miR-379-5p on UBE2E3 expression is likely to be direct. Finally, to determine if the effect of miR-379-5p on UBE2E3 is related to cellular behaviors that play a role in cancer development, we measured cell viability by resazurin assay, cell proliferation by BrdU assay, and apoptosis by caspase 3/7 activation assay. The miR-379-5p mimic and silencing UBE2E3 expression both resulted in significantly diminished cell viability, while silencing UBE2E3 demonstrated both higher proliferation and apoptotic rates. Overall, these results suggest that while the overall effect of miR-379-5p is to inhibit breast cell viability and proliferation, the effect of silencing its target UBE2E3 is more complex because it induces both cell proliferation and apoptosis.
Schroder AK
，Loy CJ
，Aiala F
，Rafique J
，Ghosh A
，Yoo LI
... -
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lncRNA SNHG4 enhanced gastric cancer progression by modulating miR-409-3p/CREB1 axis.
Gastric cancer (GC) is a globally common cancer characterized by high incidence and mortality worldwide. Advances in the molecular understanding of GC provide promising targets for GC diagnosis and therapy. Long non-coding RNAs (lncRNAs) and their downstream regulators are regarded to be implicated in the progression of multiple types of malignancies. Studies have shown that the lncRNA small nucleolar RNA host gene 4 (SNHG4) serves as a tumor promoter in various malignancies, while its function in GC has yet to be characterized. Therefore, our study aimed to explore the role and underlying mechanism of SNHG4 in GC.
We used qRT-PCR to analyze SNHG4 expression in GC tissues and cells. Kaplan-Meier analysis was used to assess the correlation between SNHG4 expression and the survival rate of GC patients. Cellular function experiments such as CCK-8, BrdU, colony formation, flow cytometry analysis, and transwell were performed to explore the effects of SNHG4 on GC cell proliferation, apoptosis, cell cycle, migration, and invasion. We also established xenograft mouse models to explore the effect of SNHG4 on GC tumor growth. Mechanically, dual luciferase reporter assay was used to verify the interaction between SNHG4 and miR-409-3p and between miR-409-3p and cAMP responsive element binding protein 1 (CREB1).
The results indicated that SNHG4 was overexpressed in GC tissues and cell lines, and was linked with poor survival rate of GC patients. SNHG4 promoted GC cell proliferation, migration, and invasion while inhibiting cell apoptosis and cell cycle arrest in vitro. The in vivo experiment indicated that SNHG4 facilitated GC tumor growth. Furthermore, SNHG4 was demonstrated to bind to miR-409-3p. Moreover, CREB1 was directly targeted by miR-409-3p. Rescue assays demonstrated that miR-409-3p deficiency reversed the suppressive impact of SNHG4 knockdown on GC cell malignancy. Additionally, miR-409-3p was also revealed to inhibit GC cell proliferation, migration, and invasion by targeting CREB1.
In conclusion, we verified that the SNHG4 promoted GC growth and metastasis by binding to miR-409-3p to upregulate CREB1, which may deepen the understanding of the underlying mechanism in GC development.
Cheng Z
，Hua Y
，Cao Y
，Qin J
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ResearchGate
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