The changeable structure and movement law of overlying strata are the maincontributor to the change of mining stress.Starting from the relevant theory of keystratum and particularly based on the theory of mine ground ...The changeable structure and movement law of overlying strata are the maincontributor to the change of mining stress.Starting from the relevant theory of keystratum and particularly based on the theory of mine ground pressure and strata control,this research proposed a new solution to mining stress problems by establishing adual-load-zone stratum structural model.Elastic foundation beam theory was used tosolve the stress of overlying strata of the dual-load-zones with superposition method,which revised the traditional calculation method of mining stress.The abnormal increaseof lead abutment pressure in the mining area was explained effectively,through which theevolution law of mining stress in the case of hard rock was obtained.The results indicatethat mining stress experiences a drastic change within the range of 50 m ahead of the coalwall due to the collapse of main roof;under the influence of main key stratum andinferior key strata,the influence range of lead abutment pressure is extended up toapproximately 120 m in the working face;this remarkable increase can be attributed tothe excessive length of sagging zone.Results from both the dual-load-zone modelexperiment and field measurement demonstrate high consistency.The model can predictthe influence range of abutment pressure effectively and thus guide the safety productionof mining.展开更多
In the last two decades, 5-fluorouracil (5-FU) is widely used in clinical practice to inhibit the fibroblasts to proliferate and improve the success rate of glaucoma-filtering surgery, but 5-FU has many toxic effects ...In the last two decades, 5-fluorouracil (5-FU) is widely used in clinical practice to inhibit the fibroblasts to proliferate and improve the success rate of glaucoma-filtering surgery, but 5-FU has many toxic effects to normal ocular tissues. The self-assembled peptide hydrogels may serve as a new class of biomaterials for applications including tissue engineering and drug delivery. How to deliver 5-FU quickly and precisely to the target sites of ocular tissue by a self-assembled peptide hydrogel remains unexplored. RGD (arginine-glycine-aspartic acid) sequence is cell attachment site in extracellular matrix (ECM). Thus, If the self-assembled peptide hydrogel containing the RGD sequence that act as a specific attachment site for the proliferated fibroblasts adhesion could be designed, after integrated 5-FU, a novel targeting drug delivery system will be put into practice in the future.展开更多
Breast cancer remains the most prevalent malignancy among women worldwide,with triple-negative breast cancer(TNBC) representing its most aggressive and lethal subtype.TNBC is characterized by high rates of recurrence ...Breast cancer remains the most prevalent malignancy among women worldwide,with triple-negative breast cancer(TNBC) representing its most aggressive and lethal subtype.TNBC is characterized by high rates of recurrence and lung metastasis after surgery,severely impacting patient quality of life.Recent studies highlight the critical role of metabolic reprogramming in driving cancer recurrence,migration,and invasion.While the underlying mechanisms remain complex and not fully elucidated,transcriptomic analyses comparing primary and metastatic breast cancer tissues from TNBC and Luminal patients have identified lysophosphatidylcholine acyltransferase 1(LPCAT1) as a key enzyme upregulated in lung metastases and TNBC.LPCAT1 is strongly associated with poor prognosis due to its activation of the TGFβ signaling pathway.This activation is driven by LPCAT1's ability to increase cellular ATP levels,fostering a high-energy state that stimulates ATPase activity.Consequently,ATP-dependent chromatin remodeling via the BAF complex,which includes double PHD finger 2(DPF2) as a critical subunit,regulates gene transcription essential for tumor progression.Through the LPCAT1-DPF2-TGFBR2 axis,TNBC cells enhance TGFβ signaling,promoting malignant behavior and metastasis.Addressing this,we developed a reduction-responsive nanoparticle platform for the systemic delivery of LPCAT1-targeted si RNA(si LPCAT1),which has shown significant efficacy in suppressing TNBC tumor growth and metastasis.These findings suggest that nanoparticle-mediated si LPCAT1 delivery represents a promising therapeutic strategy for advanced TNBC treatment.展开更多
A potential reason for the failure of tumor therapies is treatment resistance.Resistance to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and meta...A potential reason for the failure of tumor therapies is treatment resistance.Resistance to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and metastasis.The major mechanisms of therapy resistance are inhibitions of cell deaths,like apoptosis and necrosis,through drug inactivation and excretion,repair of DNA damage,tumor heterogeneity,or changes in tumor microenvironment,etc.Recent studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell death.Some ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor therapy.Notably,versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance,including directly triggering ferroptosis and feedback regulation.Herein,we provide a detailed description of the design,mechanism,and therapeutic application of ferroptosis-mediated synergistic tumor therapeutics.We also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.展开更多
The central dogma of molecular biology states that the functions of RNA revolve around protein translation.Until the last decade,most researches were geared towards characterization of RNAs as intermediaries in protei...The central dogma of molecular biology states that the functions of RNA revolve around protein translation.Until the last decade,most researches were geared towards characterization of RNAs as intermediaries in protein translation,namely,messenger RNAs(mRNAs)as temporary copies of genetic information,ribosomal RNAs(rRNAs)as a main component of ribosome,or translators of codon sequence(t RNAs).The statistical reality,however,is that these processes account for less than 2%of the genome,and insufficiently explain the functionality of 98%of transcribed RNAs.Recent discoveries have unveiled thousands of unique non-coding RNAs(ncRNAs)and shifted the perception of them from being"junk"transcriptional products to"yet to be elucidated"—and potentially monumentally important—RNAs.Most ncRNAs are now known as key regulators in various networks in which they could lead to specific cellular responses and fates.In major cancers,ncRNAs have been identified as both oncogenic drivers and tumor suppressors,indicating a complex regulatory network among these ncRNAs.Herein,we provide a comprehensive review of the various ncRNAs and their functional roles in cancer,and the pre-clinical and clinical development of nc RNA-based therapeutics.A deeper understanding of ncRNAs could facilitate better design of personalized therapeutics.展开更多
cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance ...cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.展开更多
Long non-coding RNAs(lncRNAs)play an important role in cancer metastasis.Exploring metastasis-associated lncRNAs and developing effective strategy for targeted regulation of lncRNA function in vivo are of utmost impor...Long non-coding RNAs(lncRNAs)play an important role in cancer metastasis.Exploring metastasis-associated lncRNAs and developing effective strategy for targeted regulation of lncRNA function in vivo are of utmost importance for the treatment of metastatic cancer,which however remains a big challenge.Herein,we identified a new functional lncRNA(denoted lncBCM A),which could stabilize the expression of eukaryotic translation elongation factor 1A1(eEF1A1)via antagonizing its ubiquitination to promote triple-negative breast cancer(TNBC)growth and metastasis.Based on this regulatory mechanism,an endosomal pH-responsive nanoparticle(NP)platform was engineered for systemic lncBCMA siRNA(siBCMA)delivery.This NPs-mediated siBCMA delivery could effectively silence lncBCMA expression and promote eEF1A1 ubiquitination,thereby leading to a significant inhibition of TNBC tumor growth and metastasis.These findings show that lncBCMA could be used as a potential biomarker to predict the prognosis of TNBC patients and NPs-mediated lncBCMA silencing could be an effective strategy for metastatic TNBC treatment.展开更多
Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth re...Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth receptor 2(HER2)-positive breast cancer is trastuzumab.However,resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes.To address this issue,tumor microenvironment(TME)pH-responsive nanoparticles(NPs)were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer(BCa).This nanoplatform is comprised of a methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)copolymer with a TME pH-liable linker(Meo-PEG-Dlinkm-PLGA)and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction.When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously,they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface.With the intracellular mRNA release to up-regulate PTEN expression,the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells,thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.展开更多
基金This research is supported by the National Natural Science Foundation of China(51874289)and the National Key Research and Development Program of China(2018YFC0604705)and the Fundamental Research Funds for the Central Universities 2018ZDPY05.There is no conflict of interest regarding the publication of this paper.
文摘The changeable structure and movement law of overlying strata are the maincontributor to the change of mining stress.Starting from the relevant theory of keystratum and particularly based on the theory of mine ground pressure and strata control,this research proposed a new solution to mining stress problems by establishing adual-load-zone stratum structural model.Elastic foundation beam theory was used tosolve the stress of overlying strata of the dual-load-zones with superposition method,which revised the traditional calculation method of mining stress.The abnormal increaseof lead abutment pressure in the mining area was explained effectively,through which theevolution law of mining stress in the case of hard rock was obtained.The results indicatethat mining stress experiences a drastic change within the range of 50 m ahead of the coalwall due to the collapse of main roof;under the influence of main key stratum andinferior key strata,the influence range of lead abutment pressure is extended up toapproximately 120 m in the working face;this remarkable increase can be attributed tothe excessive length of sagging zone.Results from both the dual-load-zone modelexperiment and field measurement demonstrate high consistency.The model can predictthe influence range of abutment pressure effectively and thus guide the safety productionof mining.
文摘In the last two decades, 5-fluorouracil (5-FU) is widely used in clinical practice to inhibit the fibroblasts to proliferate and improve the success rate of glaucoma-filtering surgery, but 5-FU has many toxic effects to normal ocular tissues. The self-assembled peptide hydrogels may serve as a new class of biomaterials for applications including tissue engineering and drug delivery. How to deliver 5-FU quickly and precisely to the target sites of ocular tissue by a self-assembled peptide hydrogel remains unexplored. RGD (arginine-glycine-aspartic acid) sequence is cell attachment site in extracellular matrix (ECM). Thus, If the self-assembled peptide hydrogel containing the RGD sequence that act as a specific attachment site for the proliferated fibroblasts adhesion could be designed, after integrated 5-FU, a novel targeting drug delivery system will be put into practice in the future.
基金supported by the National Natural Science Foundation of China (82173392,81874226,82072930 and 81802700)the grants from Guangdong Science and Technology Department (2024B1515040006,2021A1515111106,2020A1515011298,and 2019A1515011932)+6 种基金Guangdong Province Outstanding Youth Fund Project (2021B1515020066)Guangzhou Province Basic Research Fund (202201020576)Guangzhou Science and Technology Bureau (2024A03J0846,20210303004,and 202103000093)the Natural Science Foundation of Hunan Province (2023JJ50149)111 Project (B20056)the “Three million for Three Years” Project of the High-level Talent Special Funding Scheme of Sun Yat-Sen Memorial HospitalYouth Doctor Program Fund of the Second Affiliated Hospital,Army Medical University (2023YQB003)。
文摘Breast cancer remains the most prevalent malignancy among women worldwide,with triple-negative breast cancer(TNBC) representing its most aggressive and lethal subtype.TNBC is characterized by high rates of recurrence and lung metastasis after surgery,severely impacting patient quality of life.Recent studies highlight the critical role of metabolic reprogramming in driving cancer recurrence,migration,and invasion.While the underlying mechanisms remain complex and not fully elucidated,transcriptomic analyses comparing primary and metastatic breast cancer tissues from TNBC and Luminal patients have identified lysophosphatidylcholine acyltransferase 1(LPCAT1) as a key enzyme upregulated in lung metastases and TNBC.LPCAT1 is strongly associated with poor prognosis due to its activation of the TGFβ signaling pathway.This activation is driven by LPCAT1's ability to increase cellular ATP levels,fostering a high-energy state that stimulates ATPase activity.Consequently,ATP-dependent chromatin remodeling via the BAF complex,which includes double PHD finger 2(DPF2) as a critical subunit,regulates gene transcription essential for tumor progression.Through the LPCAT1-DPF2-TGFBR2 axis,TNBC cells enhance TGFβ signaling,promoting malignant behavior and metastasis.Addressing this,we developed a reduction-responsive nanoparticle platform for the systemic delivery of LPCAT1-targeted si RNA(si LPCAT1),which has shown significant efficacy in suppressing TNBC tumor growth and metastasis.These findings suggest that nanoparticle-mediated si LPCAT1 delivery represents a promising therapeutic strategy for advanced TNBC treatment.
基金This work was supported by the National Natural Science Foundation of China(81901794)the China Postdoctoral Science Foundation funded project(2021M693632)Guangdong Provincial Fund for Distinguished Young Scholars(2021B1515020066)。
文摘A potential reason for the failure of tumor therapies is treatment resistance.Resistance to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and metastasis.The major mechanisms of therapy resistance are inhibitions of cell deaths,like apoptosis and necrosis,through drug inactivation and excretion,repair of DNA damage,tumor heterogeneity,or changes in tumor microenvironment,etc.Recent studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell death.Some ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor therapy.Notably,versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance,including directly triggering ferroptosis and feedback regulation.Herein,we provide a detailed description of the design,mechanism,and therapeutic application of ferroptosis-mediated synergistic tumor therapeutics.We also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.
基金supported by grants from the National Key Research and Development Program of China(2016YFC1302300)the National Natural Science Foundation of China(81621004,81720108029,81930081,91940305,81874226 and 81803020)+2 种基金Guangdong Science and Technology Department(2017B030314026)Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2018GZR0201001)Guangzhou Science Technology and Innovation Commission(201803040015)partly supported by Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation。
文摘The central dogma of molecular biology states that the functions of RNA revolve around protein translation.Until the last decade,most researches were geared towards characterization of RNAs as intermediaries in protein translation,namely,messenger RNAs(mRNAs)as temporary copies of genetic information,ribosomal RNAs(rRNAs)as a main component of ribosome,or translators of codon sequence(t RNAs).The statistical reality,however,is that these processes account for less than 2%of the genome,and insufficiently explain the functionality of 98%of transcribed RNAs.Recent discoveries have unveiled thousands of unique non-coding RNAs(ncRNAs)and shifted the perception of them from being"junk"transcriptional products to"yet to be elucidated"—and potentially monumentally important—RNAs.Most ncRNAs are now known as key regulators in various networks in which they could lead to specific cellular responses and fates.In major cancers,ncRNAs have been identified as both oncogenic drivers and tumor suppressors,indicating a complex regulatory network among these ncRNAs.Herein,we provide a comprehensive review of the various ncRNAs and their functional roles in cancer,and the pre-clinical and clinical development of nc RNA-based therapeutics.A deeper understanding of ncRNAs could facilitate better design of personalized therapeutics.
基金supported by the National Natural Science Foundation of China(82171944,81873899,China)the Natural Science Foundation of Guangdong Province(2021A1515012611,China)+1 种基金the National Natural Science Foundation of China(82171952,81801719,China)Postdoctoral Research and Development Fund Project of West China Hospital(2023HXBH063,China).
文摘cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(82173392,81874226,81972471,82002819)the Thousand Talents Program for Distinguished Young Scholars(China)+7 种基金the grants from Guangdong Science and Technology Department(2019B1515120006,2020B1212060018,2020B1212030004,China)Guangzhou Science and Technology Bureau(201902020015,20210303004,China)the Key Research and Development Program of Hunan Province(2021SK2019,China)the Natural Science Foundation of Hunan Province(2022JJ40384,China)the Sun Yat-Sen University Clinical Research 5010 Program(2018007,China)the grants from Tencent Charity Foundation(SYSU-81000-20200311-0001,SYSU-05160-20200506-0001,China)the Sun Yat-Sen Clinical Research Cultivating Program(SYS-C-201801,China)the“Three million for Three Years”Project of the High-level Talent Special Funding Scheme of Sun Yat-Sen Memorial Hospital(China)。
文摘Long non-coding RNAs(lncRNAs)play an important role in cancer metastasis.Exploring metastasis-associated lncRNAs and developing effective strategy for targeted regulation of lncRNA function in vivo are of utmost importance for the treatment of metastatic cancer,which however remains a big challenge.Herein,we identified a new functional lncRNA(denoted lncBCM A),which could stabilize the expression of eukaryotic translation elongation factor 1A1(eEF1A1)via antagonizing its ubiquitination to promote triple-negative breast cancer(TNBC)growth and metastasis.Based on this regulatory mechanism,an endosomal pH-responsive nanoparticle(NP)platform was engineered for systemic lncBCMA siRNA(siBCMA)delivery.This NPs-mediated siBCMA delivery could effectively silence lncBCMA expression and promote eEF1A1 ubiquitination,thereby leading to a significant inhibition of TNBC tumor growth and metastasis.These findings show that lncBCMA could be used as a potential biomarker to predict the prognosis of TNBC patients and NPs-mediated lncBCMA silencing could be an effective strategy for metastatic TNBC treatment.
基金supported by the National Natural Science Foundation of China(82173392 and 81874226)the Thousand Talents Program for Distinguished Young Scholars,the International Scientific and Technological Cooperation Program from Guangdong Science and Technology Department(2018A050506033,China)+2 种基金the Natural Science Foundation of Guangdong Province(2019B1515120006,China)Guangzhou Science and Technology Bureau(201902020015 and 20210303004,China)the“Three million for Three Years”Project of the High-level Talent Special Funding Scheme of Sun Yat-sen Memorial Hospital.
文摘Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth receptor 2(HER2)-positive breast cancer is trastuzumab.However,resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes.To address this issue,tumor microenvironment(TME)pH-responsive nanoparticles(NPs)were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer(BCa).This nanoplatform is comprised of a methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)copolymer with a TME pH-liable linker(Meo-PEG-Dlinkm-PLGA)and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction.When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously,they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface.With the intracellular mRNA release to up-regulate PTEN expression,the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells,thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.
