Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving ...standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options.
This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18–65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III–IVA, excluding T3–4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12–16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111.
Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33–42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% 95% CI 80·4–90·6) than in the standard therapy group (75·7% 69·9–81·9), with a stratified hazard ratio of 0·50 (95% CI 0·32–0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 9% patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group.
The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma.
The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation.
For the Chinese translation of the abstract see Supplementary Materials section.
Abstract
More than 100 distinct chemical modifications to RNA have been characterized so far. However, the prevalence, mechanisms and functions of various RNA modifications remain largely unknown. To ...provide transcriptome-wide landscapes of RNA modifications, we developed the RMBase v2.0 (http://rna.sysu.edu.cn/rmbase/), which is a comprehensive database that integrates epitranscriptome sequencing data for the exploration of post-transcriptional modifications of RNAs and their relationships with miRNA binding events, disease-related single-nucleotide polymorphisms (SNPs) and RNA-binding proteins (RBPs). RMBase v2.0 was expanded with ∼600 datasets and ∼1 397 000 modification sites from 47 studies among 13 species, which represents an approximately 10-fold expansion when compared with the previous release. It contains ∼1 373 000 N6-methyladenosines (m6A), ∼5400 N1-methyladenosines (m1A), ∼9600 pseudouridine (Ψ) modifications, ∼1000 5-methylcytosine (m5C) modifications, ∼5100 2′-O-methylations (2′-O-Me), and ∼2800 modifications of other modification types. Moreover, we built a new module called 'Motif' that provides the visualized logos and position weight matrices (PWMs) of the modification motifs. We also constructed a novel module termed 'modRBP' to study the relationships between RNA modifications and RBPs. Additionally, we developed a novel web-based tool named 'modMetagene' to plot the metagenes of RNA modification along a transcript model. This database will help researchers investigate the potential functions and mechanisms of RNA modifications.
Circular RNAs (circRNAs) derived from back-spliced exons have been widely identified as being co-expressed with their linear counterparts. A single gene locus can produce multiple circRNAs through ...alternative back-splice site selection and/or alternative splice site selection; however, a detailed map of alternative back-splicing/splicing in circRNAs is lacking. Here, with the upgraded CIRCexplorer2 pipeline, we systematically annotated different types of alternative back-splicing and alternative splicing events in circRNAs from various cell lines. Compared with their linear cognate RNAs, circRNAs exhibited distinct patterns of alternative back-splicing and alternative splicing. Alternative back-splice site selection was correlated with the competition of putative RNA pairs across introns that bracket alternative back-splice sites. In addition, all four basic types of alternative splicing that have been identified in the (linear) mRNA process were found within circRNAs, and many exons were predominantly spliced in circRNAs. Unexpectedly, thousands of previously unannotated exons were detected in circRNAs from the examined cell lines. Although these novel exons had similar splice site strength, they were much less conserved than known exons in sequences. Finally, both alternative back-splicing and circRNA-predominant alternative splicing were highly diverse among the examined cell lines. All of the identified alternative back-splicing and alternative splicing in circRNAs are available in the CIRCpedia database (http://www.picb.ac.cn/rnomics/circpedia). Collectively, the annotation of alternative back-splicing and alternative splicing in circRNAs provides a valuable resource for depicting the complexity of circRNA biogenesis and for studying the potential functions of circRNAs in different cells.
To accurately predict the seasonal fluctuations of the electricity consumption of the primary economic sectors, we propose a seasonal grey model (SGM(1,1) model) based on the accumulation operators ...generated by seasonal factors. We use the proposed model to carry out an empirical analysis based on the seasonal electricity consumption data of the primary industries in China from 2010 to 2016. The results from the SGM (1,1) model are compared with those obtained using the grey model (GM(1,1)), the particle swarm optimization algorithm combines with the grey model (PSO-GM(1,1) model), and the adaptive parameter learning mechanism based seasonal fluctuation GM (1,1) model (APL-SFGM(1,1) model). The results of the comparison show that the SGM(1,1) model can effectively identify seasonal fluctuations in the electricity consumption of the primary industries and its prediction accuracy is significantly higher than those of the GM(1,1), PSO-GM(1,1) and APL-SFGM(1,1) models. The forecast results for China from 2017 to 2020 obtained using the SGM(1,1) model suggest that the electricity consumption of the primary industries is expected to increase slightly, but obvious seasonal fluctuations will still be present. It is forecasted that the annual electricity consumption in 2020 will be 107.645 TWh with an annual growth rate of 2.83%. This prediction can provide the basis for power-supply planning to ensure supply and demand balance in the electricity markets.
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•A seasonal grey model is proposed to predict quarterly electricity consumption.•The proposed model can accurately identify and predict the seasonal fluctuations.•The prediction accuracy is significantly higher than those of traditional models.•The electricity consumption of China's primary economic sectors is predicted.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects not only joints but also multiple organ systems including cardiovascular system. Endothelial dysfunction plays an important role ...in cardiovascular diseases (CVD). In RA, endothelial dysfunction exists at both the macrovascular and the microvascular levels, which is a precursor to vasculitis. This study aimed to investigate the pathogenesis of vasculitis and the therapeutic effect of CP‐25 on vasculitis in high‐fat diet (HFD) collagen‐induced arthritis (CIA) rats. Experimental groups were divided into normal group, HFD group, CIA group, HFD CIA group, CP‐25 group and MTX group. In vitro, IL‐17A was used to stimulate human umbilical vein endothelial cells (HUVECs), and then CP‐25 was used to intervene. Results showed that CP‐25 reduced global scoring (GS), arthritis index (AI), and swollen joint count (SJC) scores, improved histopathological score, reduced T cells percentage, and decreased IL‐17A and ICAM‐1 levels. Besides, CP‐25 reduced the expression of p‐STAT3 to normal levels in vascular of HFD CIA rats. In vitro, IL‐17A promoted the expression of p‐JAK1, p‐JAK2, p‐JAK3, pSTAT3, and ICAM‐1, and CP‐25 inhibited the expression of p‐JAK1, p‐JAK2, p‐JAK3, p‐STAT3, and ICAM‐1. In conclusion, CP‐25 might inhibit endothelial cell activation through inhibiting IL‐17A/JAK/STAT3 signaling pathway, which improves vasculitis in HFD CIA rats.
Long noncoding RNAs (lncRNAs) evolve more rapidly than mRNAs. Whether conserved lncRNAs undergo conserved processing, localization, and function remains unexplored. We report differing subcellular ...localization of lncRNAs in human and mouse embryonic stem cells (ESCs). A significantly higher fraction of lncRNAs is localized in the cytoplasm of hESCs than in mESCs. This turns out to be important for hESC pluripotency. FAST is a positionally conserved lncRNA but is not conserved in its processing and localization. In hESCs, cytoplasm-localized hFAST binds to the WD40 domain of the E3 ubiquitin ligase β-TrCP and blocks its interaction with phosphorylated β-catenin to prevent degradation, leading to activated WNT signaling, required for pluripotency. In contrast, mFast is nuclear retained in mESCs, and its processing is suppressed by the splicing factor PPIE, which is highly expressed in mESCs but not hESCs. These findings reveal that lncRNA processing and localization are previously under-appreciated contributors to the rapid evolution of function.
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•Subcellular localization of conserved lncRNAs is different in hESCs and mESCs•Cytoplasmic hFAST but not nuclear mFast promotes WNT signaling in hESC pluripotency•PPIE regulates distinct FAST processing in hESCs and mESCs•RNA processing and localization contribute to lncRNA functional evolution
A pair of lncRNA orthologs exhibits different subcellular localization in human and murine ESCs because of differential RNA processing, which, in turn, leads to their functional divergence in the context of pluripotency regulation. The findings highlight how conserved lncRNAs may achieve functional evolution through non-conserved RNA processing.
Many eukaryotic genes generate linear mRNAs and circular RNAs, but it is largely unknown how the ratio of linear to circular RNA is controlled or modulated. Using RNAi screening in Drosophila cells, ...we identify many core spliceosome and transcription termination factors that control the RNA outputs of reporter and endogenous genes. When spliceosome components were depleted or inhibited pharmacologically, the steady-state levels of circular RNAs increased while expression of their associated linear mRNAs concomitantly decreased. Upon inhibiting RNA polymerase II termination via depletion of the cleavage/polyadenylation machinery, circular RNA levels were similarly increased. This is because readthrough transcripts now extend into downstream genes and are subjected to backsplicing. In total, these results demonstrate that inhibition or slowing of canonical pre-mRNA processing events shifts the steady-state output of protein-coding genes toward circular RNAs. This is in part because nascent RNAs become directed into alternative pathways that lead to circular RNA production.
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•RNAi screen identifies pre-mRNA processing factors that modulate circular RNA levels•Circular RNA expression increases when core spliceosomal components are depleted•Backsplicing can occur in conditions that inhibit canonical mRNA splicing events•Readthrough transcription enables production of circular RNAs from downstream genes
Many protein-coding genes produce linear mRNAs and circular RNAs. Liang et al. find that circular RNAs become the preferred gene output when core spliceosome or transcription termination factors are depleted from cells. This is in part because nascent RNAs are directed into alternative pathways that lead to circular RNA biogenesis.
Highlights • The first study to summarize the global trends in incidence and mortality of NPC. • Decreased NPC incidence with maximum AAPCs of −5.4% in males and −4.1% in females. • Declines in NPC ...mortality rates worldwide with AAPCs varying from −0.8% to −6.5%.
Background and Aim
HOX transcript antisense intergenic RNA (HOTAIR) is a relatively well-understood RNA, which plays a central role in the pathogenesis of various tumors. The aim of the present study ...was to investigate the effect by which HOTAIR acts to influence the biological processes of colorectal cancer (CRC) through p21.
Methods
Reverse transcription quantitative polymerase chain reaction and Western blot methods were employed to provide verification regarding the changes in HOTAIR, PCNA, Ki67, p21, cyclin E, and CDK2 among the CRC tissues and cells. The correlation between the clinicopathological characteristics of patients and expression of HOTAIR and p21 was subsequently evaluated, followed by an analysis into the effects of HOTAIR on the biological processes of M5 cells.
Results
HOTAIR was found to be expressed at high levels, while p21 was determined to be at a low level among both the CRC tissues and the CRC cell lines. The expressions of HOTAIR and p21 were determined to be related to lymph node metastasis, tumor node metastasis, Dukes staging, distant metastases, histological types, and the degree of differentiation. Cells transfected with HOTAIR siRNA displayed inhibited rates of proliferation, invasion, and migration, as well as decreased cyclin E and CDK2, while apoptosis and p21 were increased.
Conclusion
The principal findings demonstrated that down-regulation of HOTAIR elicits an inhibitory effect on proliferation, invasion, and migration, while promoting the apoptosis of CRC cells through the up-regulation of p21. We believe that HOTAIR could represent a novel target for the treatment of CRC.
miR‐372/373, a cluster of stem cell‐specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the ...unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR‐372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR‐372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24‐positive cell population and promoting self‐renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA‐induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR‐372/373 and found that stemness‐related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation‐related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR‐372/373. Numerous new targets of miR‐372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR‐372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR‐372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell‐specific microRNAs in the development of metastasis and drug resistance in CRC.
The miR‐372/373 cluster can induce cancer stem cell phenotypes in colorectal cancer. Over‐expression of miR‐372/373 repress developmental pathways, including NFκB, and enhance key stemness‐related pathways, such as Nanog. A series of differentiation‐related genes, including SPOP, VDR and SETD7, were identified as targets of miR‐372/373, which were shown to be responsible for the transition from cancer cell to cancer stem‐cell phenotype.
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