ipaQTL-atlas: an atlas of intronic polyadenylation quantitative trait loci across human tissues.

Functional interpretation of disease-associated non-coding variants remains a significant challenge in the post-GWAS era. Our recent study has identified 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) and connects APA events with QTLs as a major driver of human traits and diseases. Besides 3'UTR, APA events can also occur in intron regions, and increasing evidence has connected intronic polyadenylation with disease risk. However, systematic investigation of the roles of intronic polyadenylation in human diseases remained challenging due to the lack of a comprehensive database across a variety of human tissues. Here, we developed ipaQTL-atlas (http://bioinfo.szbl.ac.cn/ipaQTL) as the first comprehensive portal for intronic polyadenylation. The ipaQTL-atlas is based on the analysis of 15 170 RNA-seq data from 838 individuals across 49 Genotype-Tissue Expression (GTEx v8) tissues and contains ∼0.98 million SNPs associated with intronic APA events. It provides an interface for ipaQTLs search, genome browser, boxplots, and data download, as well as the visualization of GWAS and ipaQTL colocalization results. ipaQTL-atlas provides a one-stop portal to access intronic polyadenylation information and could significantly advance the discovery of APA-associated disease susceptibility genes.

Amygdala signal abnormality and cognitive impairment in drug-naïve schizophrenia.

BACKGROUND: Recently studies had showed that the amygdala may take part in the cognitive impairment in schizophrenia (SC). However, the mechanism is still unclear, so we explored the relationship between the amygdala resting state magnetic resonance imaging (rsMRI) signal and cognitive function, to provide a reference for the follow-up study. METHODS: We collected 59 drug-naïve SCs and 46 healthy controls (HCs) from the Third People's Hospital of Foshan. The rsMRI technique and automatic segmentation tool were used to extract the volume and functional indicators of the SC's amygdala. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of the disease, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function. Pearson correlation analysis was used to compare the relationship between the structural and functional indicators of the amygdala and PANSS and RBANS. RESULTS: (1) There was no significant difference between SC and HC in age, gender and years of education. Compared with HC, the PANSS score of SC increased and the RBANS score decreased significantly. Meanwhile, the left amygdala volume decreased (t=-3.675, p < 0.001), and the Fractional amplitude of low-frequency fluctuations (FALFF) values of bilateral amygdala increased (tL=3.916, p < 0.001; tR=3.131, p = 0.002). (2) The volumes of the left amygdala were negatively correlated with the PANSS score (rL=-0.243, p = 0.039). While the FALFF values of the bilateral amygdala were positively correlated with the PANSS score (rL=0.257, p = 0.026; rR=0.259, p = 0.026). Bilateral amygdala volumes and FALFF values were positively correlated (rL=0.445, p < 0.001; rR=0.326, p = 0.006) and negatively correlated with RBANS score (rL=-0.284, p = 0.014; rR=-0.272, p = 0.020), respectively. CONCLUSION: The abnormal volume and function of the amygdala play important roles in the disease process of SC, and are closely related to cognitive impairment.

Predicting the risk of acute kidney injury after cardiopulmonary bypass: development and assessment of a new predictive nomogram.

BACKGROUND: Acute kidney injury (AKI) is a common and severe complication of cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to establish a model to predict the probability of postoperative AKI in patients undergoing cardiac surgery with CPB. METHODS: We conducted a retrospective, multicenter study to analyze 1082 patients undergoing cardiac surgery under CPB. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for the AKI model. Multivariable logistic regression analysis was applied to build a prediction model incorporating the feature selected in the previously mentioned model. Finally, we used multiple methods to evaluate the accuracy and clinical applicability of the model. RESULTS: Age, gender, hypertension, CPB duration, intraoperative 5% bicarbonate solution and red blood cell transfusion, urine volume were identified as important factors. Then, these risk factors were created into nomogram to predict the incidence of AKI after cardiac surgery under CPB. CONCLUSION: We developed a nomogram to predict the incidence of AKI after cardiac surgery. This model can be used as a reference tool for evaluating early medical intervention to prevent postoperative AKI.

Treatment initiation prediction by EHR mapped PPD tensor based convolutional neural networks boosting algorithm.

Electronic health records contain patient's information that can be used for health analytics tasks such as disease detection, disease progression prediction, patient profiling, etc. Traditional machine learning or deep learning methods treat EHR entities as individual features, and no relationships between them are taken into consideration. We propose to evaluate the relationships between EHR features and map them into Procedures, Prescriptions, and Diagnoses (PPD) tensor data, which can be formatted as images. The mapped images are then fed into deep convolutional networks for local pattern and feature learning. We add this relationship-learning part as a boosting module on a commonly used classical machine learning model. Experiments were performed on a Chronic Lymphocytic Leukemia dataset for treatment initiation prediction. Experimental results show that the proposed approach has better real world modeling performance than the baseline models in terms of prediction precision.

Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma.

Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.

Fractional microneedle radiofrequency device and fractional erbium-doped glass 1,565-nm device treatment of human facial photoaging: a prospective, split-face, random clinical trial.

Microneedle fractional radiofrequency (MFR) and non-ablative 1565 nm fractional laser (NAFL) have recently been introduced as new techniques to address the growing concern of facial photoaging. In this prospective randomized split-face study, we wanted to compare the safety and efficacy of MFR with that of NAFL for the treatment of facial photoaging in Asian patients. Fifteen healthy Chinese patients were enrolled for this randomized split-face study. Each patient underwent three sessions of treatment with MFR and NAFL on opposite sides of their face, one month apart. A blinded outcome assessment of the photoaging severity was performed by two independent plastic surgeons on a 5-point visual analogue scale (VAS, 0-4). Patient satisfaction was also scored based on a 5-point VAS (0 = dissatisfaction, 4 = extremely satisfied). Sagging of the nasolabial groove was evaluated using the Antera 3D camera, facial wrinkles and pores using the VISIA skin analysis system. Any adverse events that occurred during the study were also evaluated. Based on the VAS scores and results from the Antera 3D and VISIA, it was noted that there was a significant improvement in facial skin laxity, wrinkles, and pores, and lesser sagging of the nasolabial groove on both the MFR and NAFL sides of the face, compared with that of the baseline. Most patients were satisfied with the treatment and reported tolerable pain and crusting. Although no significant differences were observed between the MFR and NAFL treatments, the NAFL treatment resulted in a shorter downtime(4.56 ± 2.72d) than the MFR treatment(6.96 ± 3.27d). This study confirms the efficacy of MFR and NAFL treatments for facial skin rejuvenation in Asian patients. Furthermore, the therapies were found to be safe and well-tolerated. Our findings suggest that NAFL may be a more convenient treatment modality for facial photoaging because of its shorter downtime. However, sagging of the nasolabial groove was more improved by the MFR treatment than by the NAFL treatment.

Identification of key candidate genes in neuropathic pain by integrated bioinformatic analysis.

This study aimed to disclose differentially expressed genes (DEGs) in dorsal root ganglia (DRGs) of neuropathic pain (NP) from spared nerve injury (SNI) model, thereby identifying specific and meaningful genetic targets for the diagnosis and treatment of NP. The GSE89224 was downloaded from the GEO database. DEGs were screened using the GEO2R online tool. Functional enrichment analysis of DEGs was then performed using the DAVID and constructed using the R ggplot2 package. Protein-protein interaction (PPI) network was constructed from the STRING database and visualized in Cytoscape software. MicroRNA targeting these DEGs was obtained from the TarBase and miRTarBase database, while transcription factor (TF)-targeting DEGs were predicted from the ENCODE database, both of which utilized the visual analytics platform NetworkAnayst. Finally, a merged microRNA-TF network was constructed based on the above two networks and was then analyzed with Cytoscape. Eighty DEGs were screened, only Vstm2b and Htr3a were downregulated and 78 genes were upregulated. The real-time polymerase chain reaction was applied to validate the gene expression of the top five DEGs (Npy, Atf3, Gpr151, Sprr1a, and Cckbr) in the DRG tissue 5 days after SNI surgery. It was found that Npy, Atf3, and Sprr1a have a significant increase after SNI stimulation, while Gpr151 and Cckbr showed a slight upward trend. Functional analysis was performed on all DEGs, of which 58 biological processes were enriched by gene ontology analysis, and 11 signaling pathways were enriched by KEGG analysis. In the PPI network, Atf3, Jun, Timp, and Npy had a higher degree. Thus, combined with various bioinformatic analyses, Npy and Atf3 may serve as the prognostic and therapeutic targets of NP. Key microRNA (mmu-mir-16-5p) and TF (MEF2A) were predicted to be associated with the pathogenetic process of NP with microRNA-TF regulatory network analysis, which were also identified as key regulators in the progression of NP.

A combination of captopril challenge test after saline infusion test improves diagnostic accuracy for primary aldosteronism.

CONTEXT: The saline infusion test (SIT) is a common confirmatory test for primary aldosteronism (PA). According to the guideline, a postinfusion plasma aldosterone concentration (PAC) of 5-10 ng/dL is considered indeterminate, and recommendations for diagnostic strategies are currently limited in this situation. OBJECTIVE: To explore whether an addition of the captopril challenge test (CCT) could improve the diagnostic accuracy in patients with indeterminate SIT. METHODS: A total of 280 hypertensive patients with high risk of PA completed this study. Subjects were defined as SIT indeterminate based on their PAC post-SIT. These patients then underwent the CCT where PACs post-CCT >11 ng/dL were considered positive. Using fludrocortisone suppression test (FST) as the reference standard, diagnostic parameters including area under the receiver-operator characteristic curves (AUC), sensitivity and specificity were calculated. RESULTS: There were 65 subjects (23.2%) diagnosed as PA indeterminate after SIT. With the addition of CCT, true-positive numbers increased from 134 to 147, and false-negative numbers decreased from 27 to 14. Compared to SIT alone, a combination of SIT and CCT showed a higher AUC (0.91 [0.87,0.94] vs 0.87 [0.83,0.91], P = .041) and an increased sensitivity for the diagnosis of PA (0.91 [0.86,0.95] vs 0.83 [0.76,0.89], P = .028), while the specificity remained similar. In the subgroup with indeterminate SIT results, using PAC post-CCT resulted in a 36% higher AUC than using PAC post-SIT alone for the diagnosis of PA. CONCLUSION: For patients under investigation for possible PA who have indeterminate SIT results, an addition of CCT improves the diagnostic accuracy.

Emerging role of lncRNAs in renal fibrosis.

Fibrosis is the final common pathological feature of a wide variety of chronic kidney disease (CKD). However, an understanding of the mechanisms underlying the development of renal fibrosis remains challenging and controversial. As the current focus of molecular research, noncoding RNAs (ncRNAs), mainly microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular noncoding RNAs (circRNAs), have powerful and abundant biological functions, which essentially makes them mediators of the physiological and pathological processes of various system diseases. The role of ncRNAs in renal fibrosis has also received great attention in recent years, but most research has mainly focused on miRNAs. In fact, although a large number of studies of lncRNAs have emerged recently, the role these molecules play in renal fibrosis haven't been fully understood till now. Thus, this review discusses the discovery of lncRNAs and their biological functions in different types of renal fibrosis, as well as the imminent applications of these findings in clinical use. Undoubtedly, in the future, further understanding of the function of all types of lncRNAs will reveal large breakthroughs in the treatment of renal fibrosis.

Correction to: PTH Derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities.

An amendment to this paper has been published and can be accessed via the original article.

PTH Derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities.

BACKGROUND: Diabetic wounds are a disturbing and rapidly growing clinical problem. A novel peptide, parathyroid hormone related peptide (PTHrP-2), is assumed as multifunctional factor in angiogenesis, fibrogenesis and re-epithelization. This study aims to test PTHrP-2 efficiency and mechanism in wound healing. METHODS: Through repair phenomenon in vivo some problems were detected, and further research on their mechanisms was made. In vivo therapeutic effects of PTHrP-2 were determined by HE, Masson, microfil and immunohistochemical staining. In vitro direct effects of PTHrP-2 were determined by proliferation, migration, Vascular Endothelial Grown Factor and collagen I secretion of cells and Akt/ Erk1/2 pathway change. In vitro indirect effects of PTHrP-2 was study via exosomes. Exosomes from PTHrP-2 untreated and treated HUVECs and HFF-1 cells were insolated and identified. Exosomes were co-cultured with original cells, HUVECs or HFF-1 cells, and epithelial cells. Proliferation and migration and pathway change were observed. PTHrP-2-HUVEC-Exos were added into in vivo wound to testify its hub role in PTHrP-2 indirect effects in wound healing. RESULTS: In vivo, PTHrP-2 exerted multifunctional pro-angiogenesis, pro-firbogenesis and re-epithelization effects. In vitro, PTHrP-2 promoted proliferation and migration of endothelial and fibroblast cells, but had no effect on epithelial cells. Therefore, we tested PTHrP-2 indirect effects via exosomes. PTHrP-2 intensified intercellular communication between endothelial cells and fibroblasts and initiated endothelial-epithelial intercellular communication. PTHrP-2-HUVEC-Exos played a hub role in PTHrP-2 indirect effects in wound healing. CONCLUSION: These findings of this study indicated that PTHrP-2, a multifunctional factor, could promote wound healing via synergistic multicellular stimulating and exosomal activities.

Electron Microscopy-Based Comparison and Investigation of the Morphology of Exosomes Derived from Hepatocellular Carcinoma Cells Isolated at Different Centrifugal Speeds.

Exosomes derived from hepatocellular carcinoma (HCC) cells are nanovesicles and are involved in the occurrence and development of HCC, they also serve as important carriers and drug targets of nanodrug delivery systems. The external shape and internal structure of exosomes are important indexes of identification, and isolated intact morphology is crucial to biological function integrity. However, given their susceptibility to various influencing factors, the external shape and internal structure of exosomes derived from HCC cells remain incompletely studied. In this study, exosomes purified from HCC cells were isolated at different centrifugation speeds and examined via multiple electron microscopy (EM) techniques. The results demonstrate that exosomes possess a nearly spherical shape and bilipid membranous vesicle with a concave cavity structure containing electron-dense and coated vesicles, suggesting the possible existence of subpopulations of exosomes with specific functions. The exosomes isolated at ultracentrifugation (UC) speed (≥110,000×g) presented irregular and diverse external morphologies, indicating the effect on the integrity of the exosomes. Transforming growth factor signaling bioactive substances (TGF-ß1, S100A8, and S100A9) can be found in exosomes by performing Western blotting, showing that the internal content is associated with metastasis of HCC. These findings show that EMelectron microscopy and UC speed can affect exosome characteristics, including external shape, internal structure, and content of bioactive substances. The electron-dense and coated vesicles that had been discovered in exosomes might become new additional morphological features, which could help to improve the interpretation of experimental results and widen our understanding of exosome morphology.

Histone deacetylases up-regulate C/EBPα expression through reduction of miR-124-3p and miR-25 in hepatocellular carcinoma.

BACKGROUND: CCAAT enhancer binding protein α (C/EBPα), as an important transcription factor involved in cell proliferation, differentiation and metabolism, was up-regulated in primary hepatocellular carcinoma (HCC) and predicted poorer prognosis. In this study, we explored how histone deacetylases (HDACs) up-regulated C/EBPα in HCC. METHODS: The protein expressions of HDAC1, HDAC2 were associated with C/EBPα by immunohistochemistry staining in a HCC tissue microarray. HCC cells were then treated with HDAC inhibitors or siRNAs to determine the roles of miR-124-3p and miR-25 in the regulation of C/EBPα mRNA expression. RESULTS: Both HDAC1 and HDAC2 proteins were significantly associated with C/EBPα. Inhibition of HDAC by either pharmacological inhibitors or siRNAs decreased C/EBPα mRNA expression in dose-dependent manners in HCC cells. HDAC inhibitors reduced C/EBPα mRNA stability as shown by pmiRGLO luciferase reporter assays. HDAC inhibition consistently induced miR-124-3p and miR-25 expression. Conversely, blockage of miR-124-3p and/or miR-25 by treatment with specific synthetic inhibitors abolished C/EBPα reduction. More importantly, C/EBPα mRNA stability could be rescued by site-directed mutations of miR-124-3p or miR-25 recognition sites in the C/EBPα 3'UTR sequence. In summary, HDAC may up-regulate C/EBPα expression through miR-124-3p and miR-25 in HCC.

Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.

Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.

Varacin-1, a novel analog of varacin C, induces p53-independent apoptosis in cancer cells through ROS-mediated reduction of XIAP.

Varacin C is a promising anticancer agent and possesses acid-promoted and photo-induced DNA-damaging activities. In this study, we synthesized an analog varacin-1 (VCA-1) and examined its anticancer potentials. The results demonstrated that VCA-1 caused dose-dependent apoptotic cell death in cancer cells. Note that this action is independent of p53 status, because VCA-1 induced similar levels of apoptosis in two different panels of cell lines (HCT116 p53- wild-type vs. HCT116 p53-knockout colon cancer cells, and p53-expressing U2OS vs. p53-deficient saos2 osteosarcoma cancer cells). VCA-1-induced apoptosis was found to be mainly via the extrinsic apoptosis pathway involving caspase-8 activation and XIAP reduction. Forced over-expression of XIAP markedly prevented apoptosis, indicating its essential role in VCA-1 induced apoptosis. On the other hand, VCA-1 treatment enhanced intracellular ROS (reactive oxygen species) generation also in a p53-independent manner, and consequently promoted caspase activation. Pretreatment of N-acetyl cysteine (an antioxidant), rather than z-VAD (specific caspase inhibitor), markedly prevented XIAP reduction, suggesting that XIAP reduction may be resulted from oxidative stress. In conclusion, data from this study reveal the essential roles of ROS generation and XIAP reduction in VCA-1-induced apoptosis in cancer cells. VCA-1 may be a novel cancer therapeutic agent, especially in p53-mutant human cancers.

Optimal Design of Angular Displacement Sensor with Shared Magnetic Field Based on the Magnetic Equivalent Loop Method.

Angular displacement sensor with shared magnetic field has strong environmental adaptability and high measurement accuracy. However, its 3-D structure is multi-pole double-layer structure, using time stepping finite element method (TSFEM) to optimize the structure is time-consuming and uneconomical. Therefore, a magnetic equivalent loop method (MELM) is proposed to simplify the optimal design of sensors. By reasonably setting the node position, the mechanical structure parameters, winding coefficients and input voltage of the sensor are integrated into a mathematical model to calculate of the induced voltage. The calculation results are compared with the simulation results, and a sensor prototype is made to test the optimized effect of the MELM.

A Technique for Digital Impression and Bite Registration for a Single Edentulous Arch.

Few studies have reported the application of digital technology for the process of impression and interocclusal recordings in edentulous patients. This article describes a digitizing system for generating digital edentulous models with a jaw relationship by taking direct digital impressions and a virtual bite registration using intraoral digital scanning. A specialized scan retractor was used to make digital impressions of edentulous jaws in patients' mouths using an intraoral scanner. Virtual bite registration was obtained with optical scanning of the buccal surfaces of both jaws at the occlusal vertical dimension. The registration was then used as a reference for aligning both jaws. Digital edentulous models that include the jaw relationship would be clinically beneficial for the fabrication of complete dentures in edentulous patients.

Alterations in exosomal miRNA profile upon epithelial-mesenchymal transition in human lung cancer cell lines.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is regarded as a critical event during tumor metastasis. Recent studies have revealed changes and the contributions of proteins in/on exosomes during EMT. Besides proteins, microRNA (miRNA) is another important functional component of exosomes. We hypothesized that the miRNA profile of exosomes may change following EMT and these exosomal miRNAs may in return promote EMT, migration and invasion of cancer cells. RESULTS: The small RNA profile of exosomes was altered following EMT. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the specific miRNAs of M-exosomes have the potential to drive signal transduction networks in EMT and cancer progression. Co-culture experiments confirmed that M-exosomes can enter epithelial cells and promote migration, invasion and expression of mesenchymal markers in the recipient cells. CONCLUSION: Our results reveal changes in the function and miRNA profile of exosomes upon EMT. M-exosomes can promote transfer of the malignant (mesenchymal) phenotype to epithelial recipient cells. Further, the miRNAs specifically expressed in M-exosomes are associated with EMT and metastasis, and may serve as new biomarkers for EMT-like processes in lung cancer.

Effects of mesenchymal stem cells on solid tumor metastasis in experimental cancer models: a systematic review and meta-analysis.

BACKGROUND: It has been reported mesenchymal stem cells (MSCs) are recruited to and become integral parts of the tumor microenvironment. MSCs might have an active role in solid tumor progression, especially cancer metastasis. However, the contribution of MSCs in the process of cancer metastasis is still controversial. In this review, we performed a meta-analysis on the effects of MSCs administration on cancer metastasis based on published preclinical studies. METHODS: The PRISMA guidelines were used. A total of 42 publications met the inclusion criteria. Outcome data on the incidence and the number of cancer metastasis as well as study characteristics were extracted. Quality of the studies was assessed according to SYRCLE Risk of Bias tool. Random-effects meta-analysis was used to pool estimates. RESULTS: Of the 42 studies included, 32 reported that MSCs administration promoted outcome events (numbers or incidences of cancer metastasis), and 39 reported data suitable for meta-analysis. The median effect size (RR) was 2.04 for the incidence of cancer metastasis (95% CI 1.57-2.65, I2 = 21%), and the median effect size (SMD) was 1.23 for the number of cancer metastasis (95% CI 0.43-2.03, I2 = 89%). Heterogeneity was observed, with the greater impact based on study length and different ways of metastasis measurement and MSCs administration. CONCLUSION: Our results suggested MSCs administration increased the number and the incidence of cancer metastasis in experimental cancer models. High heterogeneity and poor reported risk of bias limit the quality of these findings. Further preclinical studies with better design and adequate reporting are still needed.