Intestinal stem cells (ISCs) are maintained by stemness signaling for precise modulation of self-renewal and differentiation under homeostasis. However, the way in which intestinal immune cells ...regulate the self-renewal of ISCs remains elusive. Here we found that mouse and human Lgr5
ISCs showed high expression of the immune cell-associated circular RNA circPan3 (originating from the Pan3 gene transcript). Deletion of circPan3 in Lgr5
ISCs impaired their self-renewal capacity and the regeneration of gut epithelium in a manner dependent on immune cells. circPan3 bound mRNA encoding the cytokine IL-13 receptor subunit IL-13Rα1 (Il13ra1) in ISCs to increase its stability, which led to the expression of IL-13Rα1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13Rα1 on crypt ISCs and activated signaling mediated by IL-13‒IL-13R, which in turn initiated expression of the transcription factor Foxp1. Foxp1 is associated with β-catenin in rendering its nuclear translocation, which caused activation of the β-catenin pathway and the maintenance of Lgr5
ISCs.
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we ...show that
N
1
-methyladenosine methylation (m
1
A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m
1
A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m
1
A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m
1
A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m
1
A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer.
“…The customary test for an observed difference…is based on an enumeration of the probabilities, on the initial hypothesis that two treatments do not differ in their effects,…of all the various ...results which would occur if the trial were repeated indefinitely with different random samples of the same size as those actually used.” –Peter Armitage (“Sequential tests in prophylactic and therapeutic trials” in Quarterly Journal of Medicine, 1954;23(91):255‐274). Randomization has been the hallmark of the clinical trial since Sir Bradford Hill adopted it in the 1946 streptomycin trial. An exploration of the early literature yields three rationales, ie, (i) the incorporation of randomization provides unpredictability in treatment assignments, thereby mitigating selection bias; (ii) randomization tends to ensure similarity in the treatment groups on known and unknown confounders (at least asymptotically); and (iii) the act of randomization itself provides a basis for inference when random sampling is not conducted from a population model. Of these three, rationale (iii) is often forgotten, ignored, or left untaught. Today, randomization is a rote exercise, scarcely considered in protocols or medical journal articles. Yet, the literature of the last century is rich with statistical articles on randomization methods and their consequences, authored by some of the pioneers of the biostatistics and statistics world. In this paper, we review some of this literature and describe very simple methods to rectify some of the oversight. We describe how randomization‐based inference can be used for virtually any outcome of interest in a clinical trial. Special mention is made of nonstandard clinical trials situations.
Biomass-carbon prepared by Kiwi peel and asymmetric carbon-based nanospheres synthesized by hydrothermally method are used as substrate to decorate NiS2 nanoparticles to obtain NiS2/BC. Dropping the ...NiS2/BC dispersions on the surface of glassy carbon electrode to improve conductivity. Then we modified the electrode with N-GOQDs and AuNPs to improve the electroactive region of the surface and the electron transfer rate. Nicotinamide was used as functional monomer, MIP was prepared on the surface of Au/N-GOQDs/NiS2/BC/GCE by electropolymerization method in presence of DA and CPZ to enhance the selectivity and sensitivity of the sensor. After extraction of the template molecule, DA and CPZ can be specifically recognized by the imprinted cavities formed on the surface of the MIP. Quantitative electrochemical analysis is performed by differential pulse voltammetry (DPV). Demonstrate the prepared Au/N-GOQDs/NiS2/BC/MIP/GCE can be used for sensitive and selective determination of DA and CPZ in human serum, urine and pharmaceutical samples.
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•A novel imprinted polymer electrochemical sensor based on AuNPs and N-GOQDs coated on NiS2/BC was proposed.•Molecularly imprinting approach used for simultaneous determination of DA and CPZ.•Highly sensitive and selective determination of DA and CPZ with LODs in nanomolar range.•This sensor was successful for determination of DA and CPZ in biological samples.
In this study, a dual template molecularly imprinted electrochemical sensor was fabricated for the simultaneous determination of dopamine (DA) and chlorpromazine (CPZ). Nitrogen-doped graphene oxide quantum dots (N-GOQDs) and gold nanoparticles (AuNPs) were deposited on a combination of biomass carbon and biomass-derived asymmetric carbon-based nanospheres decorated with NiS2 nanoparticles (NiS2/BC), and the obtained material was used to modify glass carbon electrode (GCE). The electropolymerization of nicotinamide (NA) on Au/N-GOQDs/NiS2/BC/GCE via cyclic voltammetry (CV) using NA as functional monomer and DA and CPZ as template was used to produce molecularly imprinted polymer (MIP) film. Various experimental parameters, including electropolymerization cycles, template-to-functional monomer ratio, pH value, elution time, and incubation time, were optimized. Differential pulse voltammetry (DPV) response under optimized parameters show two linear ranges for DA (0.05–8 µM and 8–40 µM), and the limit of detection (LOD) is as low as 2.8 nM (S/N = 3). CPZ had a linearity range of 0.005–2 µM with very low LOD value of 0.25 nM (S/N = 3). The prepared MIP electrochemical sensor had good reproducibility and repeatability, acceptable stability, and high selectivity for DA and CPZ. Furthermore, the sensor was used in real sample analysis of human serum, urine and pharmaceutical samples, and the result of recovery (93.9%–106.15%) and relative standard deviation (RSD) (1.5%–6.6%) indicated good practicality.
Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well ...contribute to both of these pathological properties, but the mechanisms underlying their self-renewal and maintenance are poorly understood. Here, using transcriptome microarray analysis, we identified a long noncoding RNA (lncRNA) termed lncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, lncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that lncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an lncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that lncRNAs can play in tumor growth and propagation.
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•The long noncoding RNA lncTCF7 is highly expressed in liver cancer tissues and CSCs•LncTCF7 is important for self-renewal of liver CSCs•LncTCF7 activates the Wnt signaling pathway through TCF7 expression•LncTCF7 recruits the SWI/SNF complex to activate the TCF7 promoter
Wang et al. have identified a long noncoding RNA, lncTCF7, that activates Wnt signaling to promote liver cancer stem cell self-renewal and tumor propagation. Targeting this pathway could help address the high recurrence and heterogeneity of liver cancer.
Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). However, the biology of hepatic CSCs remains largely undefined. ...Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours. LncBRM is required for the self-renewal maintenance of liver CSCs and tumour initiation. In liver CSCs, lncBRM associates with BRM to initiate the BRG1/BRM switch and the BRG1-embedded BAF complex triggers activation of YAP1 signalling. Moreover, expression levels of lncBRM together with YAP1 signalling targets are positively correlated with tumour severity of HCC patients. Therefore, lncBRM and YAP1 signalling may serve as biomarkers for diagnosis and potential drug targets for HCC.
Randomization‐based interval estimation takes into account the particular randomization procedure in the analysis and preserves the confidence level even in the presence of heterogeneity. It is ...distinguished from population‐based confidence intervals with respect to three aspects: definition, computation, and interpretation. The article contributes to the discussion of how to construct a confidence interval for a treatment difference from randomization tests when analyzing data from randomized clinical trials. The discussion covers (i) the definition of a confidence interval for a treatment difference in randomization‐based inference, (ii) computational algorithms for efficiently approximating the endpoints of an interval, and (iii) evaluation of statistical properties (ie, coverage probability and interval length) of randomization‐based and population‐based confidence intervals under a selected set of randomization procedures when assuming heterogeneity in patient outcomes. The method is illustrated with a case study.
Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase associated with numerous aspects of health and physiology. Overexpression of SIRT6 has emerged as a protector in cardiac tissues against pathologic ...cardiac hypertrophy. However, the mechanism of this protective effect is not fully understood. Here, both in vivo and in vitro results demonstrated that SIRT6 overexpression can attenuate cisplatin-induced kidney injury in terms of renal dysfunction, inflammation and apoptosis. In addition, SIRT6 knockout aggravated kidney injury caused by cisplatin. We also found that SIRT6 bound to the promoters of ERK1 and ERK2 and deacetylated histone 3 at Lys9 (H3K9) thereby inhibiting ERK1/2 expression. Furthermore, inhibition of ERK1/2 activity eliminated aggravation of kidney injury caused by SIRT6 knock out. Thus, our findings uncover the protective effect of SIRT6 on the kidney and define a new mechanism by which SIRT6 regulates inflammation and apoptosis. This may provide a new therapeutic target for kidney injury under stress.
Matrix metalloproteinase-2 (MMP-2) is a very important biomarker in blood. Presently, sensitive and selective determination of MMP-2 directly in blood samples is still a challenging job because of ...the high complexity of the sample matrix. In this work, we reported a new homogeneous biosensor for MMP-2 based on fluorescence resonance energy transfer (FRET) from upconversion phosphors (UCPs) to carbon nanoparticles (CNPs). A polypeptide chain (NH2-GHHYYGPLGVRGC-COOH) comprising both the specific MMP-2 substrate domain (PLGVR) and a π-rich motif (HHYY) was designed and linked to the surface of UCPs at the C terminus. The FRET process was initiated by the π–π interaction between the peptide and CNPs, which thus quenched the fluorescence of the donor. Upon the cleavage of the substrate by the protease at the amide bond between Gly and Val, the donor was separated from the acceptor while the π-rich motif stayed on the acceptor. As a result, the fluorescence of the donor was restored. The fluorescence recovery was found to be proportional to the concentration of MMP-2 within the range from 10–500 pg/mL in an aqueous solution. The quantification limit of this sensor was at least 1 order of magnitude lower than that of other reported assays for MMP-2. The sensor was used to determine the MMP-2 level directly in human plasma and whole blood samples with satisfactory results obtained. Owing to the hypersensitivity of the method, clinical samples of only less than 1 μL were needed for accurate quantification, which can be meaningful in MMP-2-related clinical and bioanalytical applications.
Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. Liver cancer initiating cells also called cancer stem cells ...(CSCs) play a critical role in resistance against typical therapy and high tumor-initiating potential. However, the role of the novel circular RNA (circRNA) circIPO11 in the maintenance of liver cancer initiating cells remains elusive.
CircRNAs highly conserved in humans and mice were identified from 3 primary HCC samples by circRNA array. The expression and function of circIPO11 were further evaluated by Northern blot, limiting dilution xenograft analysis, chromatin isolation by RNA purification-PCR assay (ChIRP) and HCC patient-derived tumor cells (PDC) models. CircIpo11 knockout (KO) mice were generated by a CRISPR/Cas9 technology.
CircIPO11 is highly expressed in HCC tumor tissues and liver CSCs. CircIPO11 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, circIPO11 recruits TOP1 to GLI1 promoter to trigger its transcription, leading to the activation of Hedgehog signaling. Moreover, GLI1 is also highly expressed in HCC tumor tissues and liver CSCs, and TOP1 expression levels positively correlate with the metastasis, recurrence and survival of HCC patients. Additionally, circIPO11 knockout in mice suppresses the progression of chemically induced liver cancer development.
Our findings reveal that circIPO11 drives the self-renewal of liver CSCs and promotes the propagation of HCC via activating Hedgehog signaling pathway. Antisense oligonucleotides (ASOs) against circIPO11 combined with TOP1 inhibitor camptothecin (CPT) exert synergistic antitumor effect. Therefore, circIPO11 and the Hedgehog signaling pathway may provide new potential targets for the treatment of HCC patients.
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