Summary Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest—namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial—ENTHUSE M1—in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·39–4·62, p<0·0001; reference model: 2·56, 1·85–3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified...

Premature ovarian insufficiency (POI) is clinically irreversible in women aged over 40 years. Although numerous studies have demonstrated satisfactory outcomes of mesenchymal stem cell therapy, the underlying therapeutic mechanism remains unclear. Exosomes were collected from the culture medium of human umbilical cord mesenchymal stem cells (hUMSCs) and assessed by electron microscopy and Western blot (WB) analysis. Then, exosomes were added to the culture medium of cyclophosphamide (CTX)‐damaged human granulosa cells (hGCs), and the mixture was injected into the ovaries of CTX‐induced POI model mice before detection of antiapoptotic and apoptotic gene expression. Next, the microRNA expression profiles of hUMSC‐derived exosomes (hUMSC‐Exos) were detected by small RNA sequencing. The ameliorative effect of exosomal microRNA‐17‐5P (miR‐17‐5P) was demonstrated by miR‐17‐5P knockdown before assessment of ovarian phenotype and function, reactive oxygen species (ROS) levels and SIRT7 expression. Finally, SIRT7 was inhibited or overexpressed by RNA interference or retrovirus transduction, and the protein expression of PARP1, γH2AX, and XRCC6 was analyzed. The ameliorative effect of hUMSC‐Exos on POI was validated. Our results illustrated that hUMSC‐Exos restored ovarian phenotype and function in a POI mouse model, promoted proliferation of CTX‐damaged hGCs and ovarian cells, and alleviated ROS accumulation by delivering exosomal miR‐17‐5P and inhibiting SIRT7 expression. Moreover, our findings elucidated that miR‐17‐5P repressed PARP1, γH2AX, and XRCC6 by inhibiting SIRT7. Our findings suggest a critical role for exosomal miR‐17‐5P and its downstream target mRNA SIRT7 in hUMSC transplantation therapy. This study indicates the promise of exosome‐based therapy for POI treatment.

Multiple studies have demonstrated that lncRNAs extensively participate in human cancer proliferation and metastasis. Epigenetic modification, transcriptional and posttranscriptional regulatory mechanisms are involved in lncRNA-led tumorigenesis and transfer. Recently, a novel identified homeobox (HOX) A11 antisense lncRNA, HOXA11-AS, 1,628 bp in length, has been excessively highlighted to be an essential initiator and facilitator in the process of malignant tumor proliferation and metastasis. As found in many reports, HOXA11-AS can not only act as a molecular scaffold of PRC2, LSD1 and DNMT1 to epigenetically modify chromosomes in the nucleus but also occur as ceRNA competitively sponging miRNAs in the cytoplasm. Furthermore, HOXA11-AS may function as a potential biomarker for cancer diagnosis and prognosis. In this review, we summarize the evolvement and mechanisms of HOXA11-AS in proliferation and metastasis of various human cancers.

The tissue microenvironment functions as a crucial player in carcinogenesis, and transforming growth factor-β1 (TGF-β1) within the microenvironment stimulates the formation of neoplasms. Using an in vitro model of malignancy induced by TGF-β1, we assessed the effect of evodiamine and berberine on the interaction between DNA methyltransferases (DNMTs) and target microRNAs (miRNAs) in the model. Colon tissues from neonatal rats 7 days of age were cultured and malignancy was induced by TGF-β1 in vitro for 48 h, and then the tissues were respectively treated with evodiamine and berberine for 24 h. Morphological alteration of tissues was observed by an inverted microscope, histological structures were observed using hematoxylin and eosin staining, and the expression levels of DNMTs and targeted miRNAs screened by bioinformatics software combined with Gene chip analysis in our previous study were detected by immunohistochemistry and quantified by real-time PCR. Twenty-four hours after treatment with TGF-β1, expression levels of DNMT1, DNMT3A, DNMT3B and miR-152 (target DNMT1), miR-429 (target DNMT3A) and miR-29a (target DNMT3A/3B) were markedly decreased; however, after 48 h, the expression levels of DNMT1 and DNMT3A were significantly increased, but their target miRNAs were still decreased. After treatment with a DNMT inhibitor (5-Aza-dC), expression levels of the miRNAs were increased to a larger extent, but did not reach normal levels. After treatment with berberine and evodiamine for 24 h, respectively, increased expression of DNMT1, DNMT3A, DNMT3B and miR-152, miR-429, miR-29a was noted. In conclusion, the results of the present study suggest that miRNAs can also be post-transcriptionally regulated by their corresponding DNMTs and that berberine and evodiamine regulate the expression of these genes, which provides early epigenetic evidence for the prevention and therapy of colorectal cancer.