Although 5-methylcytosine (m
C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the ...single-nucleotide resolution landscape of messenger RNA m
C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m
C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m
C 'reader' recognizing m
C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m
C methylation site in the HDGF 3' untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m
C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.
Recent realization of high sodium‐ion conductivities (>10−2 S cm−1) in inorganic solid electrolytes (ISEs) at room temperature will certainly trigger a boom in all‐solid‐state sodium batteries ...(ASS‐SBs). However, their electrochemical stable windows and compatibility to high capacity/voltage electrodes are unsatisfactory. Developing ideal ISEs that deliver high Na+ ion conductivities, good electrochemical/chemical stability, and compatible electrode/ISE interface is key for the success of high‐performance ASS‐SBs. In this review, focus is mainly on the fundamentals and strategies to optimize ASS‐SB performances from the aspects of ISE and interface, and note that interfacial issues are also ISE‐related. The latest progress in ISEs, including fundamentals of the sodium‐ion conduction mechanism, key parameters dominating the Na+ ion conduction in terms of crystal structure, lattice dynamics, point defects, and grain boundaries, and prototyping strategies for cell design, are elaborated from the perspectives of material and defect chemistry. The key challenges and future opportunities are discussed, and rational solutions are provided.
This review discusses the fundamentals of sodium ionic conduction in inorganic solid electrolytes (ISEs), identifies the key parameters dominating the sodium ionic conduction, and proposes prototyping strategies for both solid electrolyte and full cell design, from the perspectives of materials and defect chemistry. The key challenges and future opportunities for all‐solid‐state sodium batteries using ISEs are also discussed in detail.
Ulcerative colitis (UC) is a chronic recurrent intestinal inflammatory disease characterized by high incidence and young onset age. Recently, there have been some interesting findings in the ...pathogenesis of UC. The mucus barrier, which is composed of a mucin complex rich in O-glycosylation, not only provides nutrients and habitat for intestinal microbes but also orchestrates the taming of germs. In turn, the gut microbiota modulates the production and secretion of mucins and stratification of the mucus layers. Active bidirectional communication between the microbiota and its 'slimy' partner, the mucus barrier, seems to be a continually performed concerto, maintaining homeostasis of the gut ecological microenvironment. Any abnormalities may induce a disorder in the gut community, thereby causing inflammatory damage. Our review mainly focuses on the complicated communication between the mucus barrier and gut microbiome to explore a promising new avenue for UC therapy.
Solid state potassium (K) metal batteries are intriguing in grid‐scale energy storage, benefiting from the low cost, safety, and high energy density. However, their practical applications are impeded ...by poor K/solid electrolyte (SE) interfacial contact and limited capacity caused by the low K self‐diffusion coefficient, dendrite growth, and intrinsically low melting point/soft features of metallic K. Herein, a fused‐modeling strategy using potassiophilic carbon allotropes molted with K is demonstrated that can enhance the electrochemical performance/stability of the system via promoting K diffusion kinetics (2.37 × 10−8 cm2 s−1), creating a low interfacial resistance (≈1.3 Ω cm2), suppressing dendrite growth, and maintaining mechanical/thermal stability at 200 °C. A homogeneous/stable K stripping/plating is consequently implemented with a high current density of 2.8 mA cm−2 (at 25 °C) and a record‐high areal capacity of 11.86 mAh cm−2 (at 0.2 mA cm−2). The enhanced K diffusion kinetics contribute to sustaining intimate interfacial contact, stabilizing the stripping/plating at high current densities. Full cells coupling ultrathin K–C composite anodes (≈50 µm) with Prussian blue cathodes and β/β″‐Al2O3 SEs deliver a high energy density of 389 Wh kg−1 with a retention of 94.4% after 150 cycles and fantastic performances at −20 to 120 °C.
An ultrathin K–10% reduced graphene oxide anode is constructed, delivering promoted K diffusion kinetics and mechanical/thermal stability at 200 °C, which creates an interfacial resistance (≈1.3 Ω cm2) with a current density of 2.8 mA cm−2 at 25 °C and an areal capacity of 11.86 mAh cm−2, enabling solid state potassium metal batteries operating at −20 to 120 °C.
Compound Kushen Injection (CKI) is a Traditional Chinese Medicine (TCM) preparation that has been clinically used in China to treat various types of solid tumours. Although several studies have ...revealed that CKI can inhibit the proliferation of hepatocellular carcinoma (HCC) cell lines, the active compounds, potential targets and pathways involved in these effects have not been systematically investigated. Here, we proposed a novel idea of "main active compound-based network pharmacology" to explore the anti-cancer mechanism of CKI. Our results showed that CKI significantly suppressed the proliferation and migration of SMMC-7721 cells. Four main active compounds of CKI (matrine, oxymatrine, sophoridine and N-methylcytisine) were confirmed by the integration of ultra-performance liquid chromatography/mass spectrometry (UPLC-MS) with cell proliferation assays. The potential targets and pathways involved in the anti-HCC effects of CKI were predicted by a network pharmacology approach, and some of the crucial proteins and pathways were further validated by western blotting and metabolomics approaches. Our results indicated that CKI exerted anti-HCC effects via the key targets MMP2, MYC, CASP3, and REG1A and the key pathways of glycometabolism and amino acid metabolism. These results provide insights into the mechanism of CKI by combining quantitative analysis of components, network pharmacology and experimental validation.
Spermatogenesis is a fundamental process in male reproductive biology and depends on precise balance between self-renewal and differentiation of male germ cells. However, the regulative factors for ...controlling the balance are poorly understood. In this study, we examined the roles of
and
in male germ cell development by generating their mutants with Crispr/Cas9 technology in zebrafish.
mutant zebrafish displayed a female-biased sex ratio, and both male and female
mutants developed hypertrophic gonads due to uncontrolled proliferation and impaired differentiation of germ cells. A large number of proliferating spermatogonium-like cells were observed within testicular lobules of the
-mutated testes, and they were demonstrated to be both Vasa- and PH3-positive. Moreover, the average number of Sycp3- and Vasa-positive cells in the
mutants was significantly lower than in wild-type testes, suggesting a severely impaired differentiation of male germ cells. Conversely, all the
-mutated testes displayed severe testicular developmental defects and gradual loss of all Vasa-positive germ cells by inhibiting their self-renewal and inducing apoptosis. In addition, several germ cell and Sertoli cell marker genes were significantly downregulated, whereas a prominent increase of Insl3-positive Leydig cells was revealed by immunohistochemical analysis in the disorganized
-mutated testes. Our data suggest that
might act as a guardian to control the balance between proliferation and differentiation of male germ cells, whereas
might be required for the maintenance, self-renewal, and differentiation of male germ cells. Significantly, this study unravels novel functions of
gene in fish.
Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn lots of attention in the pathogenesis of human cancers. However, the role of circRNAs in cancer cells ...epithelial-mesenchymal transition (EMT) remains unclear. In this study, we aimed to identify novel circRNAs that regulate urothelial carcinoma of the bladder (UCB) cells' EMT and explored their regulatory mechanisms and clinical significance in UCBs.
We first screened circRNA expression profiles using a circRNA microarray in paired UCB and normal tissues, and then studied the clinical significance of an upregulated circRNA, circPRMT5, in a large cohort of patients with UCB. We further investigated the functions and underlying mechanisms of circPRMT5 in UCB cells' EMT. Moreover, we evaluated the regulation effect of circPRMT5 on miR-30c, and its target genes,
and
, in two independent cohorts from our institute and The Cancer Genome Atlas (TCGA).
We demonstrated that upregulated expression of circPRMT5 was positively associated with advanced clinical stage and worse survival in patients with UCB. We further revealed that circPRMT5 promoted UCB cell's EMT via sponging miR-30c. Clinical analysis from two independent UCB cohorts showed that the circPRMT5/miR-30c/SNAIL1/E-cadherin pathway was essential in supporting UCB progression. Importantly, we identified that circPRMT5 was upregulated in serum and urine exosomes from patients with UCB, and significantly correlated with tumor metastasis.
CircPRMT5 exerts critical roles in promoting UCB cells' EMT and/or aggressiveness and is a prognostic biomarker of the disease, suggesting that circPRMT5 may serve as an exploitable therapeutic target for patients with UCB.
Sorafenib is the most recommended first‐line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have ...demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC‐mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+/VETC–) was investigated. Kaplan‐Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio HR = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC‐ patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+, but not VETC–, patients. Further mechanistic investigations showed that VETC+ and VETC– HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal‐regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC‐pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC– irrespective of levels of pERK/EC‐pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC– HCCs may not result from activation of Raf/mitogen‐activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+, but not VETC–, patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.
Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial–mesenchymal transition (EMT) has ...been considered a key event in metastasis. Based on histological examination of serial HCC sections and three‐dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb‐like networks. The presence of VETC (VETC+) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell–derived angiopoietin‐2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin‐2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC– xenografts but did not affect that of VETC+ ones, although silencing of Snail or Slug substantially reduced the in vitro migration of both VETC+ and VETC– HCC cells. In contrast to human VETC– cases, EMT signatures were rarely observed in VETC+ cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream. Conclusion: Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs. (Hepatology 2015;62:452–465
The standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti–programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has ...revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP.
ORIENT-12, a randomized, double-blind, phase 3 study, was conducted at 42 centers in the People’s Republic of China (ClinicalTrials.gov, number NCT03629925). Patients with locally advanced or metastatic sqNSCLC and without EGFR-sensitive mutations or ALK rearrangements were enrolled in the study. The stratification factors included clinical stage, choice of platinum, and programmed death-ligand 1 tumor proportion score. The patients, investigators, research staff, and sponsor team were masked to treatment assignment. Eligible patients were randomized 1:1, using an integrated web-response system, to receive sintilimab 200 mg or placebo plus GP every 3 weeks for four or six cycles, followed by sintilimab or placebo as maintenance therapy until disease progression or 2 years. The primary end point was progression-free survival (PFS), assessed by an independent radiographic review committee.
Between September 25, 2018 and July 26, 2019, a total of 543 patients were screened, of whom 357 patients were randomized to the sintilimab-GP group (n = 179) and the placebo-GP group (n = 178). After a median follow-up period of 12.9 months, sintilimab-GP continued to reveal a meaningful improvement in PFS than placebo-GP (hazard ratio = 0.536 95% confidence interval: 0.422–0.681, p < 0.00001). Treatment-emergent adverse events of grade 3 or worse occurred in 86.6% patients in the sintilimab-GP group and in 83.1% in the placebo-GP group. The incidence of treatment-emergent adverse event leading to death was 4.5% and 6.7% in the two treatment groups, respectively.
Regarding PFS, sintilimab plus GP reveals clinical benefit than GP alone as first-line therapy in patients with locally advanced or metastatic sqNSCLC. The toxicity was acceptable, and no new unexpected safety signals were observed.
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