Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness an...Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.展开更多
Nanofluidic devices have turned out to be exemplary systems for investigating fluidic transport properties in a highly restricted area, where the electrostatic interactions or chemical reactions between nanochannel an...Nanofluidic devices have turned out to be exemplary systems for investigating fluidic transport properties in a highly restricted area, where the electrostatic interactions or chemical reactions between nanochannel and flowing species strongly dominate the ions and flow transport. Numerous nanofluidic devices have recently been explored to manipulate ion currents and construct electronic devices. Enlightened by electronic field effect transistors, utilizing the electric field effect of nanopore nanochannels has also been adopted to develop versatile nanofluidic devices. Here, we report a nanopore-based nanofluidic unijunction transistor composed of a conical glass nanopipette with the biomaterial polydopamine (PDA) coated at its outer surface. The asfabricated nanofluidic device exhibited negative differential resistance (NDR) and ion current oscillation (ICO) in ionic transport. The pre-doped copper ions in the PDA moved toward the tip as increasing the potential, having a robust shielding effect on the charge of the tip, thus affecting the surface charge density of the nanopore in the working zone. Finite element simulation based on a continuum model coupled with Stokes-Brinkman and Poisson-Nernst-Planck (PNP) equations revealed that the fluctuations in charge density remarkably affect the transport of ionic current in the nanofluidic device. The as-prepared nanofluidic semiconductor device was a ready-to-use equipment that required no additional external conditions. Our work provides a versatile and convenient way to construct nanofluidic electronic components;we believe by taking advantage of advanced surface modification methods, the oscillation frequency of the unijunction transistors could be controlled on demand, and more nanofluidic devices with resourceful functions would be exploited.展开更多
Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells.However,little is known about its regulatory roles in gene expression and cell fate determination.Here,we confirm that gly...Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells.However,little is known about its regulatory roles in gene expression and cell fate determination.Here,we confirm that glycolytic metabolism and lactate production decrease during the differentiation of mouse embryonic stem cells(mESCs).Importantly,acidic pH due to lactate accumulation can transiently prevent the silencing of mESC self-renewal in differentiation conditions.Furthermore,acidic pH partially blocks the differentiation of human ESCs(hESCs).Mechanistically,acidic pH downregulates AGO1 protein and de-represses a subset of mRNA targets of miR-290/302 family of microRNAs which facilitate the exit of naive pluripotency state in mESCs.Interestingly,AGO1 protein is also downregulated by acidic pH in cancer cells.Altogether,this study provides insights into the potential function and underlying mechanism of acidic pH in pluripotent stem cells(PSCs).展开更多
Splice-switching antisense oligonucleotides(ASOs)and engineered U7 small nuclear ribonucleoprotein(U7 Sm OPT)are the most commonly used methods for exon skipping.However,challenges remain,such as limited organ deliver...Splice-switching antisense oligonucleotides(ASOs)and engineered U7 small nuclear ribonucleoprotein(U7 Sm OPT)are the most commonly used methods for exon skipping.However,challenges remain,such as limited organ delivery and repeated dosing for ASOs and unknown risks of by-products produced by U7 Sm OPT.Here,we showed that antisense circular RNAs(AS-circRNAs)can effectively mediate exon skipping in both minigene and endogenous transcripts.We also showed a relatively higher exon skipping efficiency at the tested Dmd minigene than U7 Sm OPT.AS-circRNA specifically targets the precursor mRNA splicing without off-target effects.Moreover,AS-circRNAs with adeno-associated virus(AAV)delivery corrected the open reading frame and restored the dystrophin expression in a mouse model of Duchenne muscular dystrophy.In conclusion,we develop an alternative method for regulating RNA splicing,which might be served as a novel tool for genetic disease treatment.展开更多
基金supported by the Project on InterGovernmental International Scientific and Technological Innovation Cooperation in National Key Projects of Research and Development Plan (No. 2019YFE0106400)the National Natural Science Foundation of China (No. 81771875)。
文摘Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.
基金supported by the National Natural Science Foundation of China(Nos.22374145 and 21675146)the Jilin Province Science Technology Development Plan Project(No.20230508075RC)the Youth Innovation Promotion Association CAS(No.2021224).
文摘Nanofluidic devices have turned out to be exemplary systems for investigating fluidic transport properties in a highly restricted area, where the electrostatic interactions or chemical reactions between nanochannel and flowing species strongly dominate the ions and flow transport. Numerous nanofluidic devices have recently been explored to manipulate ion currents and construct electronic devices. Enlightened by electronic field effect transistors, utilizing the electric field effect of nanopore nanochannels has also been adopted to develop versatile nanofluidic devices. Here, we report a nanopore-based nanofluidic unijunction transistor composed of a conical glass nanopipette with the biomaterial polydopamine (PDA) coated at its outer surface. The asfabricated nanofluidic device exhibited negative differential resistance (NDR) and ion current oscillation (ICO) in ionic transport. The pre-doped copper ions in the PDA moved toward the tip as increasing the potential, having a robust shielding effect on the charge of the tip, thus affecting the surface charge density of the nanopore in the working zone. Finite element simulation based on a continuum model coupled with Stokes-Brinkman and Poisson-Nernst-Planck (PNP) equations revealed that the fluctuations in charge density remarkably affect the transport of ionic current in the nanofluidic device. The as-prepared nanofluidic semiconductor device was a ready-to-use equipment that required no additional external conditions. Our work provides a versatile and convenient way to construct nanofluidic electronic components;we believe by taking advantage of advanced surface modification methods, the oscillation frequency of the unijunction transistors could be controlled on demand, and more nanofluidic devices with resourceful functions would be exploited.
基金This work was supported by the National Key Research and Development Program of China(2016YFA0100701 and 2018YFA0107601)the National Natural Science Foundation of China(91640116,91940302,31622033,and 31821091)the Fundamental Research Funds for the Central Universities(3332018008).
文摘Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells.However,little is known about its regulatory roles in gene expression and cell fate determination.Here,we confirm that glycolytic metabolism and lactate production decrease during the differentiation of mouse embryonic stem cells(mESCs).Importantly,acidic pH due to lactate accumulation can transiently prevent the silencing of mESC self-renewal in differentiation conditions.Furthermore,acidic pH partially blocks the differentiation of human ESCs(hESCs).Mechanistically,acidic pH downregulates AGO1 protein and de-represses a subset of mRNA targets of miR-290/302 family of microRNAs which facilitate the exit of naive pluripotency state in mESCs.Interestingly,AGO1 protein is also downregulated by acidic pH in cancer cells.Altogether,this study provides insights into the potential function and underlying mechanism of acidic pH in pluripotent stem cells(PSCs).
基金the National Natural Science Foundation of China(grant numbers 81930121 and 82125008)STI2030-Major projects(grant number 2021ZD0200900)+1 种基金the National Key Research and Development Program of China(grant numbers 2018YFA0801403 and 2018YFA0107902)the Natural Science Foundation of Yunnan Province(grant numbers 202001BC070001 and 202102AA100053)。
文摘Splice-switching antisense oligonucleotides(ASOs)and engineered U7 small nuclear ribonucleoprotein(U7 Sm OPT)are the most commonly used methods for exon skipping.However,challenges remain,such as limited organ delivery and repeated dosing for ASOs and unknown risks of by-products produced by U7 Sm OPT.Here,we showed that antisense circular RNAs(AS-circRNAs)can effectively mediate exon skipping in both minigene and endogenous transcripts.We also showed a relatively higher exon skipping efficiency at the tested Dmd minigene than U7 Sm OPT.AS-circRNA specifically targets the precursor mRNA splicing without off-target effects.Moreover,AS-circRNAs with adeno-associated virus(AAV)delivery corrected the open reading frame and restored the dystrophin expression in a mouse model of Duchenne muscular dystrophy.In conclusion,we develop an alternative method for regulating RNA splicing,which might be served as a novel tool for genetic disease treatment.
