In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long non...In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.展开更多
This study investigated the potential of oleaginous yeast Rhodotorula glutinis utilizing pulp and paper wastewater effluents as cultivation media for the sustainable production of microbial lipids as biodiesel feedsto...This study investigated the potential of oleaginous yeast Rhodotorula glutinis utilizing pulp and paper wastewater effluents as cultivation media for the sustainable production of microbial lipids as biodiesel feedstock. R. glutinis is oleaginous yeast, which has the ability to produce significant quantities of intercellular lipids in the form of triacylglycerols. Yeast lipids are a promising potential feedstock for biodiesel production due to similar fatty acid composition to plant oils. The effect of various carbon sources on biomass production, lipid accumulation, substrate utilization, and fatty acid composition using R. glutinis in the pulp and paper wastewater media was studied. The pulp and paper wastewater was supplemented with glucose, xylose, and glycerol as carbon sources under nitrogen-limited conditions. The maximum lipid productions of 1.3 - 2.9 g•L–1, which corresponded to the intracellular lipid contents of 8% - 15% cell dry weight (CDW), were obtained under various carbon substrates. A kinetic study of the batch fermentation was performed in a 3 L aerobic batch fermenter to describe the cell growth, lipid accumulation, and substrate utilization process, and the kinetic parameter was estimated. The fatty acid profile of oleaginous yeast was rich in palmitic, oleic, and linoleic acids and comparable to vegetable oils. Thus, the results of this study indicated that pulp and paper wastewater could be used to produce lipids as biodiesel feedstock.展开更多
Starch containing wastewaters from the food and feed industry have been identified as potential cheap carbon sources for the production of microbial lipids. Due to its high potential lipid content the oleaginous yeast...Starch containing wastewaters from the food and feed industry have been identified as potential cheap carbon sources for the production of microbial lipids. Due to its high potential lipid content the oleaginous yeast Rhodotorula glutinis is often used for fermentations in this field. Moreover it is investigated in the context of microbial carotenoid production, which also requires a cheap source of carbon. Thus, the ability of R. glutinis (ATCC 15125TM) to degrade and utilize soluble starch for the production of lipids has been assessed in this study. While glucose and fructose were readily consumed from the medium, starch was only slightly reduced in one treatment. The yield of fatty acid methyl esters (FAME) was graduated corresponding to the initial sugar contents, with the highest FAME yield (1.5 g·L-1) at the highest initial sugar content. In the treatment that contained starch as single carbon source, no FAME production was realized. Accordingly, if starchy wastewaters should be used for microbial cultivation with R. glutinis, an enzymatic or chemical pretreatment for starch hydrolysis should be applied, to increase the availability of this carbon source.展开更多
Highly sensitive stimuli-responsive luminescent materials are crucial for appli-cations in optical sensing,security,and anticounterfeiting.Here,we report two zero-dimensional(0D)copper(I)halides,(TEP)_(2)Cu_(2)Br_(4),...Highly sensitive stimuli-responsive luminescent materials are crucial for appli-cations in optical sensing,security,and anticounterfeiting.Here,we report two zero-dimensional(0D)copper(I)halides,(TEP)_(2)Cu_(2)Br_(4),(TEP)_(2)Cu_(4)Br_(6),and 1D(TEP)_(3)Ag_(6)Br_(9),which are comprised of isolated[Cu_(2)Br_(4)]^(2-),[Cu_(4)Br_(6)]^(2-),and[Ag_(6)Br_(9)]3-polyanions,respectively,separated by TEP^(+)(tetraethylphosphonium[TEP])cations.(TEP)_(2)Cu_(2)Br_(4) and(TEP)_(2)Cu_(4)Br_(6) demonstrate greenish-white and orange-red emissions,respectively,with near unity photoluminescence quantum yields,while(TEP)_(3)Ag_(6)Br_(9) is a poor light emitter.Optical spectroscopy mea-surements and density-functional theory calculations reveal that photoemissions of these compounds originate from self-trapped excitons due to the excited-state distor-tions in the copper(I)halide units.Crystals of Cu(I)halides are radioluminescence active at room temperature under both X-andγ-rays exposure.The light yields up to 15,800 ph/MeV under 662 keVγ-rays of ^(137)Cs suggesting their potential for scintillation applications.Remarkably,(TEP)_(2)Cu_(2)Br_(4) and(TEP)_(2)Cu_(4)Br_(6) are inter-convertible through chemical stimuli or reverse crystallization.In addition,both compounds demonstrate luminescence on-off switching upon thermal stimuli.The sensitivity of(TEP)_(2)Cu_(2)Br_(4) and(TEP)_(2)Cu_(4)Br_(6) to the chemical and thermal stimuli coupled with their ultrabright emission allows their consideration for applications such as solid-state lighting,sensing,information storage,and anticounterfeiting.展开更多
Selective laser melting(SLM) is an attractive rapid prototyping technology for the fabrication of metallic components with complex structure and high performance. Aluminum alloy, one of the most pervasive structural m...Selective laser melting(SLM) is an attractive rapid prototyping technology for the fabrication of metallic components with complex structure and high performance. Aluminum alloy, one of the most pervasive structural materials, is well known for high specific strength and good corrosion resistance. But the poor laser formability of aluminum alloy restricts its application. There are problems such as limited processable materials, immature process conditions and metallurgical defects on SLM processing aluminum alloys. Some efforts have been made to solve the above problems. This paper discusses the current research status both related to the scientific understanding and technology applications. The paper begins with a brief introduction of basic concepts of aluminum alloys and technology characterization of laser selective melting. In addition, solidification theory of SLM process and formation mechanism of metallurgical defects are discussed. Then, the current research status of microstructure, properties and heat treatment of SLM processing aluminum alloys is systematically reviewed respectively. Lastly, a future outlook is given at the end of this review paper.展开更多
Xenoliths of garnet and spinel-garnet 1herzolite from Mingxi, Eastern China have been studied in terms of comprehensive methods of mineralogy, petrology, fabrics, mierostructures and infrared spectrum. The temperature...Xenoliths of garnet and spinel-garnet 1herzolite from Mingxi, Eastern China have been studied in terms of comprehensive methods of mineralogy, petrology, fabrics, mierostructures and infrared spectrum. The temperature and pressure equilibration of the xenolith have been calculated using the TEMPEST program with the two-pyroxene geothermometer of Bertrand and Mercier (1985) combined with the geobarometer of Nickel and Green (1985). The temperature and pressure of xenoliths range from^1300 K at 1. 9 GPa (60 km) to ~1500 K at 2. 6 GPa (80 km). The geotherm inferred from xenolith is excellently consistent with the measured surface heat flow (70 mW/m2) in Mingxi. A character of geothermal curve and conductive type suggest that these xenoliths are from the lithosphere, not from the asthenosphere. The geotherm and mierostructures and preferred orientations of minerals in the xenolith are consistent with tecon-ic thinning of the lithosphere in the present-day extensional back-arc environment.展开更多
Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosom...Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD.Within PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils.The aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and cathepsins.Since these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive consequences.Methods We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical analyses.Results We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the lysosome.Using a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein levels.Conclusions Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal cathepsins.It appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.展开更多
Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening...Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening out to immunomodulatory drugs or metabolic targeting compounds,drug resistance is still ultimately universally fatal.In this brief review,we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation,focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment.In this way,with a better understanding of both targetable mutations in combination with the metabolism,smarter drugs may be designed to combat cancer drug resistance.展开更多
Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Str...Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Stromal cells can adopt new phenotypes to promote tumor cell invasion.Adeep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions.In this review,we describe the tumor microenvironment(TME)components and associated therapeutics.We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these pathways.These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling pathways.We also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the TME.In addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies.We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response.Overall,this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME,highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology.We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors,such as the inhabitant human microbiome,which have the potential to modulate TME biology and drug responses.展开更多
A large body of experimental work has established that athermal colloid/polymer mixtures undergo a sequence of transitions from a disordered fluid state to a colloidal crystal to a second disordered phase with increas...A large body of experimental work has established that athermal colloid/polymer mixtures undergo a sequence of transitions from a disordered fluid state to a colloidal crystal to a second disordered phase with increasing polymer concentration.These transitions are driven by polymer-mediated interparticle attraction,which is a function of both the polymer density and size.It has been posited that the disordered state at high polymer density is a consequence of strong interparticle attractions that kinetically inhibit the formation of the colloidal crystal,i.e.,the formation of a non-equilibrium gel phase interferes with crystallization.Here we use molecular dynamics simulations and density functional theory on polymers and nanoparticles(NPs)of comparable size and show that the crystal-disordered phase coexistence at high polymer density for sufficiently long chains corresponds to an equilibrium thermodynamic phase transition.While the crystal is,indeed,stabilized at intermediate polymer density by polymer-induced intercolloid attractions,it is destabilized at higher densities because long chains lose significant configurational entropy when they are forced to occupy all of the crystal voids.Our results are in quantitative agreement with existing experimental data and show that,at least in the nanoparticle limit of sufficiently small colloidal particles,the crystal phase only has a modest range of thermodynamic stability.展开更多
基金supported in part by grants from the US NIH grant CA130966, CA158911 to S. Y. Chengthe Zell Scholar Award from the Zell Family Foundation and funds from Northwestern Brain Tumor Institute and Department of Neurology at Northwestern University Feinberg School of Medicine to S. Y. Chengthe Brain Cancer Research Award from the James S. McDonnell Foundation to B. Hu
文摘In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.
文摘This study investigated the potential of oleaginous yeast Rhodotorula glutinis utilizing pulp and paper wastewater effluents as cultivation media for the sustainable production of microbial lipids as biodiesel feedstock. R. glutinis is oleaginous yeast, which has the ability to produce significant quantities of intercellular lipids in the form of triacylglycerols. Yeast lipids are a promising potential feedstock for biodiesel production due to similar fatty acid composition to plant oils. The effect of various carbon sources on biomass production, lipid accumulation, substrate utilization, and fatty acid composition using R. glutinis in the pulp and paper wastewater media was studied. The pulp and paper wastewater was supplemented with glucose, xylose, and glycerol as carbon sources under nitrogen-limited conditions. The maximum lipid productions of 1.3 - 2.9 g•L–1, which corresponded to the intracellular lipid contents of 8% - 15% cell dry weight (CDW), were obtained under various carbon substrates. A kinetic study of the batch fermentation was performed in a 3 L aerobic batch fermenter to describe the cell growth, lipid accumulation, and substrate utilization process, and the kinetic parameter was estimated. The fatty acid profile of oleaginous yeast was rich in palmitic, oleic, and linoleic acids and comparable to vegetable oils. Thus, the results of this study indicated that pulp and paper wastewater could be used to produce lipids as biodiesel feedstock.
文摘Starch containing wastewaters from the food and feed industry have been identified as potential cheap carbon sources for the production of microbial lipids. Due to its high potential lipid content the oleaginous yeast Rhodotorula glutinis is often used for fermentations in this field. Moreover it is investigated in the context of microbial carotenoid production, which also requires a cheap source of carbon. Thus, the ability of R. glutinis (ATCC 15125TM) to degrade and utilize soluble starch for the production of lipids has been assessed in this study. While glucose and fructose were readily consumed from the medium, starch was only slightly reduced in one treatment. The yield of fatty acid methyl esters (FAME) was graduated corresponding to the initial sugar contents, with the highest FAME yield (1.5 g·L-1) at the highest initial sugar content. In the treatment that contained starch as single carbon source, no FAME production was realized. Accordingly, if starchy wastewaters should be used for microbial cultivation with R. glutinis, an enzymatic or chemical pretreatment for starch hydrolysis should be applied, to increase the availability of this carbon source.
文摘Highly sensitive stimuli-responsive luminescent materials are crucial for appli-cations in optical sensing,security,and anticounterfeiting.Here,we report two zero-dimensional(0D)copper(I)halides,(TEP)_(2)Cu_(2)Br_(4),(TEP)_(2)Cu_(4)Br_(6),and 1D(TEP)_(3)Ag_(6)Br_(9),which are comprised of isolated[Cu_(2)Br_(4)]^(2-),[Cu_(4)Br_(6)]^(2-),and[Ag_(6)Br_(9)]3-polyanions,respectively,separated by TEP^(+)(tetraethylphosphonium[TEP])cations.(TEP)_(2)Cu_(2)Br_(4) and(TEP)_(2)Cu_(4)Br_(6) demonstrate greenish-white and orange-red emissions,respectively,with near unity photoluminescence quantum yields,while(TEP)_(3)Ag_(6)Br_(9) is a poor light emitter.Optical spectroscopy mea-surements and density-functional theory calculations reveal that photoemissions of these compounds originate from self-trapped excitons due to the excited-state distor-tions in the copper(I)halide units.Crystals of Cu(I)halides are radioluminescence active at room temperature under both X-andγ-rays exposure.The light yields up to 15,800 ph/MeV under 662 keVγ-rays of ^(137)Cs suggesting their potential for scintillation applications.Remarkably,(TEP)_(2)Cu_(2)Br_(4) and(TEP)_(2)Cu_(4)Br_(6) are inter-convertible through chemical stimuli or reverse crystallization.In addition,both compounds demonstrate luminescence on-off switching upon thermal stimuli.The sensitivity of(TEP)_(2)Cu_(2)Br_(4) and(TEP)_(2)Cu_(4)Br_(6) to the chemical and thermal stimuli coupled with their ultrabright emission allows their consideration for applications such as solid-state lighting,sensing,information storage,and anticounterfeiting.
基金sponsored by National Key Research and Development Program "Additive Manufacturing and Laser Manufacturing" (No. 2016YFB1100101)Natural and Science Foundation of China (Grant Nos. 51775208, 51505166)+4 种基金Hubei Science Fund for Distinguished Young Scholars (No. 0216110085)Wuhan Morning Light Plan of Youth Science and Technology (No. 0216110066)Graduates’ Innovation Fund, Huazhong University of Science and Technology (No. 5003110027)Fundamental Research Funds for the Central University (No. 2017JYCXJJ004)the Academic frontier youth team at Huazhong University of Science and Technology (HUST)
文摘Selective laser melting(SLM) is an attractive rapid prototyping technology for the fabrication of metallic components with complex structure and high performance. Aluminum alloy, one of the most pervasive structural materials, is well known for high specific strength and good corrosion resistance. But the poor laser formability of aluminum alloy restricts its application. There are problems such as limited processable materials, immature process conditions and metallurgical defects on SLM processing aluminum alloys. Some efforts have been made to solve the above problems. This paper discusses the current research status both related to the scientific understanding and technology applications. The paper begins with a brief introduction of basic concepts of aluminum alloys and technology characterization of laser selective melting. In addition, solidification theory of SLM process and formation mechanism of metallurgical defects are discussed. Then, the current research status of microstructure, properties and heat treatment of SLM processing aluminum alloys is systematically reviewed respectively. Lastly, a future outlook is given at the end of this review paper.
文摘Xenoliths of garnet and spinel-garnet 1herzolite from Mingxi, Eastern China have been studied in terms of comprehensive methods of mineralogy, petrology, fabrics, mierostructures and infrared spectrum. The temperature and pressure equilibration of the xenolith have been calculated using the TEMPEST program with the two-pyroxene geothermometer of Bertrand and Mercier (1985) combined with the geobarometer of Nickel and Green (1985). The temperature and pressure of xenoliths range from^1300 K at 1. 9 GPa (60 km) to ~1500 K at 2. 6 GPa (80 km). The geotherm inferred from xenolith is excellently consistent with the measured surface heat flow (70 mW/m2) in Mingxi. A character of geothermal curve and conductive type suggest that these xenoliths are from the lithosphere, not from the asthenosphere. The geotherm and mierostructures and preferred orientations of minerals in the xenolith are consistent with tecon-ic thinning of the lithosphere in the present-day extensional back-arc environment.
基金supported by the Deutsche Forschungsgemeinschaft(DFG),Bonn,Germany(SFB877,project B11,Grant no.:125440785)the Interdisciplinary Center for Clinical Research(IZKF)at the University Hospital of the University of Erlangen-Nuremberg(Jochen-Kalden funding programme N8)Research reported in this publication was partly supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS092823 and RF1NS109157.
文摘Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD.Within PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils.The aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and cathepsins.Since these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive consequences.Methods We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical analyses.Results We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the lysosome.Using a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein levels.Conclusions Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal cathepsins.It appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.
文摘Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening out to immunomodulatory drugs or metabolic targeting compounds,drug resistance is still ultimately universally fatal.In this brief review,we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation,focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment.In this way,with a better understanding of both targetable mutations in combination with the metabolism,smarter drugs may be designed to combat cancer drug resistance.
基金National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT),Grant/Award Number:NRF-2022R1A2C2005057。
文摘Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Stromal cells can adopt new phenotypes to promote tumor cell invasion.Adeep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions.In this review,we describe the tumor microenvironment(TME)components and associated therapeutics.We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these pathways.These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling pathways.We also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the TME.In addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies.We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response.Overall,this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME,highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology.We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors,such as the inhabitant human microbiome,which have the potential to modulate TME biology and drug responses.
基金supported by the Office of Science of the U.S.Department of Energy under Contract No.DE-AC02-05CH11231the Advanced Scientific Computing Research(ASCR)Leadership Computing Challenge(ALCC)Financial support was received from the National Science Foundation(Collaborative Research Award CBET-1403049 at Columbia and CBET-1402166 at Princeton)is gratefully acknowledged.
文摘A large body of experimental work has established that athermal colloid/polymer mixtures undergo a sequence of transitions from a disordered fluid state to a colloidal crystal to a second disordered phase with increasing polymer concentration.These transitions are driven by polymer-mediated interparticle attraction,which is a function of both the polymer density and size.It has been posited that the disordered state at high polymer density is a consequence of strong interparticle attractions that kinetically inhibit the formation of the colloidal crystal,i.e.,the formation of a non-equilibrium gel phase interferes with crystallization.Here we use molecular dynamics simulations and density functional theory on polymers and nanoparticles(NPs)of comparable size and show that the crystal-disordered phase coexistence at high polymer density for sufficiently long chains corresponds to an equilibrium thermodynamic phase transition.While the crystal is,indeed,stabilized at intermediate polymer density by polymer-induced intercolloid attractions,it is destabilized at higher densities because long chains lose significant configurational entropy when they are forced to occupy all of the crystal voids.Our results are in quantitative agreement with existing experimental data and show that,at least in the nanoparticle limit of sufficiently small colloidal particles,the crystal phase only has a modest range of thermodynamic stability.