Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal.

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer. SIGNIFICANCE: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets.

GDF15 Promotes Cardiac Fibrosis and Proliferation of Cardiac Fibroblasts via the MAPK/ERK1/2 Pathway after Irradiation in Rats.

Ionizing radiation exposure is associated with a risk of cardiac fibrosis; however, the underlying molecular mechanism remains unclear. Growth/differentiation factor-15 (GDF15), a fibroblast factor, is a divergent member of the transforming growth factor ß superfamily. Next-generation sequencing analyses has revealed that Gdf15 is increased in cardiac fibroblasts during radiation-induced fibrosis. However, the role of Gdf15 in cardiac fibrosis remains unclear. In this study, we demonstrated that the upregulated expression of GDF15 in newborn rat cardiac fibroblasts and adult rats after irradiation could induce fibrosis, which was confirmed by the increased cell proliferation rate and the increased expression of fibrosis markers (Col1α and αSMA) in newborn rat cardiac fibroblasts after transfection with Gdf15 in vitro. Conversely, the downregulation of GDF15 inhibited cardiac fibrosis, as confirmed by G2/M-cell cycle arrest, suppression of cell proliferation, and low levels of Col1α and αSMA expression. We also found that suppressing the expression of Gdf15 in cardiac fibroblasts could lead to a decrease in CDK1 and inhibit phosphorylation of ERK1/2. Thus, GDF15 might promote cardiac fibroblast fibrosis through the MAPK/ERK1/2 pathway and thus contribute to the pathogenesis of radiation-induced heart disease.

miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts.

BACKGROUND: Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. METHODS: We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. RESULTS: DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation-the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

Radix Angelica Sinensis and Radix Hedysari Ultrafiltration Extract Protects against X-Irradiation-Induced Cardiac Fibrosis in Rats.

Radiation-induced myocardial fibrosis (RIMF) is the main pathological change associated with radiation-induced heart toxicity after radiation therapy in patients with thoracic tumors. There is an antifibrosis effect of Radix Angelica Sinensis and Radix Hedysari (RAS-RH) ultrafiltration extract from Danggui Buxue decoction (DBD) in X-irradiation-induced rat myocardial fibrosis, and this study aimed to investigate whether that effect correlated with apoptosis and oxidative stress damage in primary rat cardiac fibroblasts; further, the potential mechanisms were also explored. In this study, we first found that the RAS-RH antifibrosis effect was associated with the upregulation of microRNA-200a and the downregulation of TGF-ß1/smad3 and COL1α. In addition, we also found that the antifibrosis effect of RAS-RH was related to the induction of apoptosis in primary rat cardiac fibroblasts and to the prevention of damage caused by reactive oxygen species (ROS). Interestingly, primary rat cardiac fibroblasts exposed to X-ray radiation underwent apoptosis less frequently in the absence of RAS-RH. Therefore, RAS-RH has the ability to protect against fibrosis, which could be occurring through the induction of apoptosis and the resistance to oxidative stress in rats with X-irradiation-induced myocardial fibrosis; thus, in a model of RIMF, RAS-RH acts against X-irradiation-induced cardiac toxicity.

Therapeutic effect of angelica and its compound formulas for hypertension and the complications: Evidence mapping.

BACKGROUND: Hypertension is one of the common diseases, which brings heavy burden to human race. Currently, western medication is in absolutely dominant position in the treatment of hypertension, but it maintains for a short time and there are various side effects and drug tolerance. Therefore, Chinese medicine has attracted great attention in the treatment field of hypertension, and angelica is one of the most frequently used herbs. OBJECTIVES: In order to give some inspiration to researches in these fields, this article presents the current research status of angelica and its compound formulas treating hypertension and its complications with evidence mapping. METHODS: Main databases were systematically searched, and researches about angelica or its compound formulas containing angelica treating hypertension or its complications were included. EXCEL 2013 was used to integrate and process the data, and the result is showed intuitively with the bubble diagram. RESULTS: 49 RCTs were included after screening. The articles recruited were published with a rising trend along with time. Of the 49 RCTs, there is the outcome measure of general the efficacy in the result part in 34 RCTs (69.4%), and all the clinical effective rate in the angelica intervention group is significantly higher than the control group. There is the outcome measure of reduction of MAP in the result part in 28 RCTs, and 27 RCTs (96.4%) showed that the angelica intervention group is significantly improved than the control group while 1 (3.6%) showed no significant differences. There is the outcome measure of efficacy of target organ protection in the result part in 26 RCTs, and 25 RCTs (96.2%) showed that there is significant difference between the angelica intervention group and the control group. Of the 49 RCTs, there is the outcome measure of adverse effects in the result part in 17 RCTs. 14 RCTs (82.4%) reported no adverse effects, 2 RCTs (11.8%) reported adverse effects rate as lower than 10%, and 1 RCT (7.1%) reported adverse effects rate as higher than 40%. CONCLUSION: Current research with low quality has revealed that angelica is effective in reduction of MAP and target organ protection and the adverse effects rate is low, and the effectiveness and safety of angelica needs to be proved by further researches with high quality. Researches of high quality are needed to provide scientific evidence for angelica in treating hypertension and its complications.

Efficacy and safety of oxaliplatin-based regimen versus cisplatin-based regimen in the treatment of gastric cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: Cisplatin played an important role in the treatment of gastric cancer (GC). Oxaliplatin has been shown to be at least as effective as cisplatin for GC, with less toxicity and a better tolerability profile. We performed a meta-analysis to compare the efficacy and safety of oxaliplatin-based regimen versus cisplatin-based regimen in the treatment of GC. METHODS: Databases of CNKI, CBM, VIP, Wanfang, PubMed, Embase, Cochrane Library were searched for eligible literatures from their establishments to November 2018. Randomized controlled trials that compared the efficacy and safety of oxaliplatin-based regimen with that of cisplatin-based regimen in the treatment of GC were included. Statistical analyses were calculated using RevMan 5.3 software. RESULTS: Seven randomized controlled trials including 2297 patients were included. Compared with cisplatin-based regimen intervention in GC, oxaliplatin-based regimen treatment was able to significantly improve the partial response rate (OR = 1.26, 95% CI 1.07-1.49; p = 0.007), disease progression rate (OR = 0.41, 95% CI 0.25-0.66; p = 0.0002) and 1-year survival (OR = 1.25, 95% CI 1.00-1.56; p = 0.05). The toxicities of hematopoietic system were significantly higher in cisplatin-based regimen group (OR = 0.6, 95% CI 0.46-0.79; p = 0.0002), while oxaliplatin-based regimen group had higher neurosensory toxicity (OR = 2.21, 95% CI 1.52-3.21; p < 0.0001), In addition, gastrointestinal toxicity was similar between the two groups (OR = 1.01, 95% CI 0.5-2.01; p = 0.27). CONCLUSIONS: Compared with cisplatin-based regimen, oxaliplatin-based regimen treatment has an obvious advantage in patients with GC with acceptable tolerance.

The effects of Radix Angelica Sinensis and Radix Hedysari ultrafiltration extract on X-irradiation-induced myocardial fibrosis in rats.

Radix Angelica Sinensis and Radix Hedysari are traditional Chinese medicines that are used for preventing and treating various diseases. This study aimed to investigate the effect and possible underlying mechanisms of Radix Angelica Sinensis and Radix Hedysari ultrafiltration extract (RAS-RH) on X-irradiation-induced cardiac fibrosis in rats. Our data demonstrated that (a) a single dose of total body irradiation (TBI) at 8 Gy resulted in cardiac fibrosis, whereas the control hearts exhibited less collagen and fibrosis. RAS-RH mitigated these morphological injuries. (b) TBI resulted in an increase in the serum levels of transforming growth factor ß1 (TGF-ß1) and troponin-I (TnI). RAS-RH inhibited the release of TBI-induced serum TGF-ß1 and the TnI levels. (c) TBI inhibited the apoptosis of primary rat cardiac fibroblasts, whereas RAS-RH induced the apoptosis of primary rat cardiac fibroblasts after X- irradiation. (d) TBI resulted in an increase in the expression of osteopontin (OPN), c-fos, c-jun, miRNA-21 and collagen1α (COL1α) in primary rat cardiac fibroblasts, and RAS-RH mitigated the TBI-induced increased expression of OPN, c-jun, miRNA-21 and COL1α. In conclusion, these results demonstrate that RAS-RH exerts antifibrotic effects possibly through inducing the apoptosis of fibroblasts, inhibiting the release of serum TGF-ß1, reducing the levels of serum TnI and reducing the expression of OPN, c-jun, miRNA-21 and COL1α. Therefore, RAS-RH may potentially be developed as a medical countermeasure for the mitigation of radiation-induced myocardial fibrosis.