Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD...Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.展开更多
Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thu...Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thus involved in the pathogenesis of various diseases.In the tumor microenvironment,besides killing tumor cells by phagocytosis or activating anti-tumor immunity by tumor antigen presentation,myeloid cells could execute protumor efficacies through myeloid checkpoints by interacting with counter-receptors on other immune cells or cancer cells.In summary,myeloid checkpoints may be promising therapeutic targets for cancer immunotherapy.展开更多
Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy pre...Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.展开更多
Structured illumination microscopy(SIM)has been widely used in live-cell superresolution(SR)imaging.However,conventional physical model-based SIM SR reconstruction algorithms are prone to artifacts in handling raw ima...Structured illumination microscopy(SIM)has been widely used in live-cell superresolution(SR)imaging.However,conventional physical model-based SIM SR reconstruction algorithms are prone to artifacts in handling raw images with low signal-to-noise ratios(SNRs).Deep-learning(DL)-based methods can address this challenge but may lead to degradation and hallucinations.By combining the physical inversion model with a total deep variation(TDV)regularization,we propose a hybrid restoration method(TDV-SIM)that outperforms conventional or DL methods in suppressing artifacts and hallucinations while maintaining resolutions.We demonstrate the performance superiority of TDV-SIM in restoring actin filaments,endoplasmic reticulum,and mitochondrial cristae from extremely low SNR raw images.Thus TDV-SIM represents the ideal method for prolonged live-cell SR imaging with minimal exposure and photodamage.Overall,TDV-SIM proves the power of integrating model-based reconstruction methods with DL ones,possibly leading to the rapid exploration of similar strategies in high-fidelity reconstructions of other microscopy methods.展开更多
Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we ...Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.展开更多
Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to...Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.展开更多
Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates ...Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates of cancer increase exponentially with age,and their underlying causes are both related to cellular dysfunction.Studying these commonalities is not only key to unlocking cancer therapies,but it may also inspire us to find interventions that delay the aging process itself.展开更多
FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progressio...FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.展开更多
Cancer immunology has witnessed remarkable development over the past century.In the early 20^(th) century,William Coley embarked on pioneering efforts to activate the immune system against cancer using heat-killed Str...Cancer immunology has witnessed remarkable development over the past century.In the early 20^(th) century,William Coley embarked on pioneering efforts to activate the immune system against cancer using heat-killed Streptococcus pyogenes and Serratia marcescens^([1]).These attempts yielded varying clinical outcomes,some of which were notably successful,providing early evidence of the immune system’s potential in combating cancer.Moving into the mid-20th century,Dr.Lewis Thomas and Dr.Macfarlane Burnet introduced the concept“immune surveillance”^([2]).This theory proposed that the immune systemconstantlymonitors the body,identifying and eliminating emerging cancer cells to prevent them from developing into full-fledged tumors.This concept laid the foundation for future research in cancer immunology.Simultaneously,the concept of immune evasion emerged,emphasizing how cancer cells can elude immune detection and destruction,enabling them to proliferate and spread within the body.Thus,understanding and overcoming these mechanisms of immune escape became a pivotal focus of cancer immunotherapy.展开更多
Nowadays,according to estimates from the World Health Organization(WHO),cancer still ranks as the top leading cause of death disease worldwide[1].In case of the rapid growing of the cancer incidence and mortality,the ...Nowadays,according to estimates from the World Health Organization(WHO),cancer still ranks as the top leading cause of death disease worldwide[1].In case of the rapid growing of the cancer incidence and mortality,the global cancer burden is expected to increase about 50%in the next twenty years[1].Considering the complexity of main risk fac-tors for cancer,efforts to uncover the underlying mechanism of tumorigenesis and establish the molecular classification models for prevention are critical for global cancer control.展开更多
Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,w...Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.展开更多
Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and...Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.展开更多
METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Her...METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Here,we report that METTL3 is both interacted with and acetylated at lysine 177 by the acetyltransferase PCAF and deacetylated by SIRT3.Neither the methyltransferase activity nor the stability of METTL3 is affected by its acetylation at K177.Importantly,acetylation of METTL3 blocks its interaction with EIF3H,a subunit of the translation initiation factor,thereby reducing mRNA translation efficiency.Interestingly,acetylation of METTL3 responds to oxidative stress.Mechanistically,oxidative stress enhances the interaction of PCAF with METTL3,increases METTL3 acetylation,and suppresses the interaction of METTL3 with EIF3H,thereby decreasing the translation efficiency of ribosomes and inhibiting cell proliferation.Altogether,we suggest a mechanism by which oxidative stress regulates RNA translation efficiency by the modulation of METTL3 acetylation mediated by PCAF.展开更多
As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).Thi...As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.展开更多
As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we s...As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we stand tall amidst the constant churn of scientific discovery,witnessing firsthand the tireless efforts of researchers,clinicians,and healthcare professionals who relentlessly push the boundaries of medical knowledge.展开更多
The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.As...The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.展开更多
The long battle with cancer began centuries ago and despite many victories,the overall incidence continues to rise and it sometimes feels like that we are losing the war.The high rates and mortality of cancer have bro...The long battle with cancer began centuries ago and despite many victories,the overall incidence continues to rise and it sometimes feels like that we are losing the war.The high rates and mortality of cancer have brought an increasing burden to society and so defeating the disease remains an urgent and unmet clinical need.In recent years,there has been a profound development of new knowledge and technologies that are widely employed in cancer research across multiple disciplines and even moreso,across the world.In modern times,it is hard to keep up with these breakthroughs,especially when they occur in varying regions.To address this,we are delighted to announce the launch of Malignancy Spectrum(MSP)in a bid to bring global advances in these disciplines together in one place.展开更多
Gastric cancer is one of the most common malignancies with poor prognosis.The use of organoids to simulate gastric cancer has rapidly developed over the past several years.Patient-derived gastric cancer organoids serv...Gastric cancer is one of the most common malignancies with poor prognosis.The use of organoids to simulate gastric cancer has rapidly developed over the past several years.Patient-derived gastric cancer organoids serve as in vitro models that closely mimics donor characteristics,offering new opportunities for both basic and applied research.The“Human Gastric Cancer Organoid”is part of a series of guidelines for human gastric cancer organoids in China,jointly drafted by experts from the Chinese Society for Cell Biology and its branches,and initially released on October 29,2024.This standard outlines terminology,technical requirements,assessment protocols,and applies to production,evaluation procedures,and quality control for human gastric cancer organoids.The publication of this guideline aims to assist institutions in endorsing,establishing,and applying best practices,advancing the international standardiza-tion of human gastric cancer organoids for clinical development and therapeutic application.展开更多
Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.H...Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.Here,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient survival.Functionally,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells.CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition.Mechanistically,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT pathway.CCL22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells.The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.展开更多
Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subseq...Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and cancers.In normal myeloid cells,LILRB4 regulates intrinsic cell activation and differentiation.In disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various diseases.In summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.展开更多
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1304504)National Natural Science Foundation of China(No.82293633 and 82270180)。
文摘Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.
基金Imported Scholar Project and Startup from Peking University Health Science Center(BMU2021YJ063 to MD)the Biotechnology Innovation Plan from Beijing Sungen Biomedical Technology Co.,Ltd(2022066 to MD)the Excellent Young Scientists Fund Program(overseas)from National Natural Science Fund(HY2021-7 to MD)。
文摘Myeloid checkpoints are receptors on the myeloid cell surface which can mediate inhibitory signals to modulate anti-tumor immune activities.They can either inhibit cellular phagocytosis or suppress T cells and are thus involved in the pathogenesis of various diseases.In the tumor microenvironment,besides killing tumor cells by phagocytosis or activating anti-tumor immunity by tumor antigen presentation,myeloid cells could execute protumor efficacies through myeloid checkpoints by interacting with counter-receptors on other immune cells or cancer cells.In summary,myeloid checkpoints may be promising therapeutic targets for cancer immunotherapy.
基金Beijing Natural Science Foundation,Grant/Award Number:L222145 and L222030Emerging Engineering Interdisciplinary Project and the Fundamental Research Funds for the Central Universities,Grant/Award Number:PKU2022XGK008Peking University Medicine Fund of Fostering Young Scholars’Scientific&Technological Innovation,Grant/Award Number:BMU2022PY010。
文摘Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.
基金support by grants from the National Science and Technology Major Project Program(Grant Nos.2021YFA1100201,2022YFF0712500,and 2022YFC3400600)the National Natural Science Foundation of China(Grant Nos.92054301,81925022,92150301,32170691,62103071,and 31901061)+5 种基金the Beijing Natural Science Foundation(Grant No.Z20J00059)the Lingang Laboratory(Grant No.LG-QS-202206-06)Clinical Medicine Plus X-Young Scholars Project,Peking University,the Fundamental Research Funds for the Central Universities,the Natural Science Foundation of Chongqing(Grant No.cstc2021jcyj-msxmX0526)the Science and Technology Research Program of Chongqing Municipal Education Commission(Grant No.KJQN202100630)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDA16021200)the High-Performance Computing Platform of Peking University.
文摘Structured illumination microscopy(SIM)has been widely used in live-cell superresolution(SR)imaging.However,conventional physical model-based SIM SR reconstruction algorithms are prone to artifacts in handling raw images with low signal-to-noise ratios(SNRs).Deep-learning(DL)-based methods can address this challenge but may lead to degradation and hallucinations.By combining the physical inversion model with a total deep variation(TDV)regularization,we propose a hybrid restoration method(TDV-SIM)that outperforms conventional or DL methods in suppressing artifacts and hallucinations while maintaining resolutions.We demonstrate the performance superiority of TDV-SIM in restoring actin filaments,endoplasmic reticulum,and mitochondrial cristae from extremely low SNR raw images.Thus TDV-SIM represents the ideal method for prolonged live-cell SR imaging with minimal exposure and photodamage.Overall,TDV-SIM proves the power of integrating model-based reconstruction methods with DL ones,possibly leading to the rapid exploration of similar strategies in high-fidelity reconstructions of other microscopy methods.
基金supported by the National Natural Science Foundations of China 82230030 and 81871492(Y.L.),82201020(Y.W),and 82100980(S.S.J)the Beijing Natural Science Foundation JL23002(Y.L.)and 7214305(S.S.J)+6 种基金the Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)the Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Ten-Thousand Talents Program QNBJ2019-2(Y.L.)the Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)Beijing Nova Program Z211100002121043(Y.W.)China National Postdoctoral Program for Innovative Talents BX2021022(Y.W.),BX20200020(S.S.J)China Postdoctoral Science Foundation 2021M700281(Y.W.)。
文摘Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.
基金supported by the National Natural Science Foundation of China(81988101,81830086,and 81972243)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081)+3 种基金Suzhou Top-Notch Talent Groups(ZXD2022003)Major Program of Shenzhen Bay Laboratory(S201101004)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088).
文摘Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.
基金supported by NSFC(32170756)National Key R&D Program of China(2023YFF1205103)。
文摘Throughout our life journey,two unstoppable forces shape our existence:the specter of aging and cancer.Seemingly unrelated,these phenomena are more intertwined than we might think[1].The incidence and mortality rates of cancer increase exponentially with age,and their underlying causes are both related to cellular dysfunction.Studying these commonalities is not only key to unlocking cancer therapies,but it may also inspire us to find interventions that delay the aging process itself.
基金supported by grants from the National Natural Science Foundation of China(Nos.82172972,81972609,81472734,31170711,81773199,81730071,81972616,81230051,and 81670626)the Beijing Natural Science Foundation(Nos.202084,7171005,7120002,and 7202080).
文摘FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.
基金supported by the National Natural Science Foundation of China(91942307).
文摘Cancer immunology has witnessed remarkable development over the past century.In the early 20^(th) century,William Coley embarked on pioneering efforts to activate the immune system against cancer using heat-killed Streptococcus pyogenes and Serratia marcescens^([1]).These attempts yielded varying clinical outcomes,some of which were notably successful,providing early evidence of the immune system’s potential in combating cancer.Moving into the mid-20th century,Dr.Lewis Thomas and Dr.Macfarlane Burnet introduced the concept“immune surveillance”^([2]).This theory proposed that the immune systemconstantlymonitors the body,identifying and eliminating emerging cancer cells to prevent them from developing into full-fledged tumors.This concept laid the foundation for future research in cancer immunology.Simultaneously,the concept of immune evasion emerged,emphasizing how cancer cells can elude immune detection and destruction,enabling them to proliferate and spread within the body.Thus,understanding and overcoming these mechanisms of immune escape became a pivotal focus of cancer immunotherapy.
文摘Nowadays,according to estimates from the World Health Organization(WHO),cancer still ranks as the top leading cause of death disease worldwide[1].In case of the rapid growing of the cancer incidence and mortality,the global cancer burden is expected to increase about 50%in the next twenty years[1].Considering the complexity of main risk fac-tors for cancer,efforts to uncover the underlying mechanism of tumorigenesis and establish the molecular classification models for prevention are critical for global cancer control.
基金supported by the National Natural Science Foundation of China (81972842, 82373082, 81988101, 82173152)
文摘Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.
基金Y.Yin including the National Natural Science Foundation of China(82030081 and 81874235)the National Key Research and Development Program of China(2021YFA1300601)the Shenzhen High-level Hospital Construction Fund and Shenzhen Basic Research Key Project(JCYJ20220818102811024).
文摘Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.
基金supported by the National Key Research and Development Program of China(2022YFA1104003,2021YFC2501003)the National Natural Science Foundation of China(82230094,81972616,81730071)+1 种基金Peking University Medicine Sailing Program for Young Scholars'Scientific&Technological Innovation(BMU2024YFJHPY004)the Fundamental Research Funds for the Central Universities。
文摘METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity.METTL3 enhances RNA translation independently of its catalytic activity.However,the underlying mechanism is still elusive.Here,we report that METTL3 is both interacted with and acetylated at lysine 177 by the acetyltransferase PCAF and deacetylated by SIRT3.Neither the methyltransferase activity nor the stability of METTL3 is affected by its acetylation at K177.Importantly,acetylation of METTL3 blocks its interaction with EIF3H,a subunit of the translation initiation factor,thereby reducing mRNA translation efficiency.Interestingly,acetylation of METTL3 responds to oxidative stress.Mechanistically,oxidative stress enhances the interaction of PCAF with METTL3,increases METTL3 acetylation,and suppresses the interaction of METTL3 with EIF3H,thereby decreasing the translation efficiency of ribosomes and inhibiting cell proliferation.Altogether,we suggest a mechanism by which oxidative stress regulates RNA translation efficiency by the modulation of METTL3 acetylation mediated by PCAF.
基金supported by National Key Research and Development Program of China 2023YFC3404600National Natural Science Foundation of China grant(82371848)。
文摘As a key sensor of double-stranded DNA(dsDNA),cyclic GMP-AMP synthase(cGAS)detects cytosolic dsDNA and initiates the synthesis of 2′3′cyclic GMP-AMP(cGAMP)that activates the stimulator of interferon genes(STING).This finally promotes the production of type I interferons(IFN-I)that is crucial for bridging innate and adaptive immunity.Recent evidence show that several antitumor therapies,including radiotherapy(RT),chemotherapy,targeted therapies and immunotherapies,activate the cGAS-STING pathway to provoke the antitumor immunity.In the last decade,the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry.However,up to now,none of STING agonists have been approved for clinical use.Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node(dLN),research on the optimal way to activate STING in tumor microenvironment(TME)appears to be a promising direction.Moreover,besides enhancing IFN-I signaling,the cGAS-STING pathway also plays roles in senescence,autophagy,apoptosis,mitotic arrest,and DNA repair,contributing to tumor development and metastasis.In this review,we summarize the recent advances on cGAS-STING pathway’s response to antitumor therapies and the strategies involving this pathway for tumor treatment.
文摘As the crisp air of a new year washes over us,carrying with it the scent of possibilities and the whispers of unfinished endeavors,it is time for reflection and,of course,renewed dedication.Here at Medical Review,we stand tall amidst the constant churn of scientific discovery,witnessing firsthand the tireless efforts of researchers,clinicians,and healthcare professionals who relentlessly push the boundaries of medical knowledge.
基金National Natural Science Foundation of China (82000003)China Postdoctoral Science Foundation (2023M743039)National Key Research and Development Program of China (2022YFC3401400).
文摘The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.
文摘The long battle with cancer began centuries ago and despite many victories,the overall incidence continues to rise and it sometimes feels like that we are losing the war.The high rates and mortality of cancer have brought an increasing burden to society and so defeating the disease remains an urgent and unmet clinical need.In recent years,there has been a profound development of new knowledge and technologies that are widely employed in cancer research across multiple disciplines and even moreso,across the world.In modern times,it is hard to keep up with these breakthroughs,especially when they occur in varying regions.To address this,we are delighted to announce the launch of Malignancy Spectrum(MSP)in a bid to bring global advances in these disciplines together in one place.
基金National Natural Science Foundation of China(31988101 to Y.‑G.C.,32300586 to Y.L.W.)National Key Research and Development Program of China(2023YFA1800603 to Y.‑G.C)+1 种基金Major Project of Guangzhou National Laboratory(GZNL2023A02008 to Y.L.W.)Young Talent Support Project of Guangzhou Association for Science and Technology(QT2024‑019 to Y.L.W.).
文摘Gastric cancer is one of the most common malignancies with poor prognosis.The use of organoids to simulate gastric cancer has rapidly developed over the past several years.Patient-derived gastric cancer organoids serve as in vitro models that closely mimics donor characteristics,offering new opportunities for both basic and applied research.The“Human Gastric Cancer Organoid”is part of a series of guidelines for human gastric cancer organoids in China,jointly drafted by experts from the Chinese Society for Cell Biology and its branches,and initially released on October 29,2024.This standard outlines terminology,technical requirements,assessment protocols,and applies to production,evaluation procedures,and quality control for human gastric cancer organoids.The publication of this guideline aims to assist institutions in endorsing,establishing,and applying best practices,advancing the international standardiza-tion of human gastric cancer organoids for clinical development and therapeutic application.
基金This work was supported by the National Natural Science Foundation of China(81988101,81830086 and 81972243)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-081)+2 种基金Funding by the Major Program of Shenzhen Bay Laboratory(S201101004)the Guangdong Basic and Applied Basic Research Foundation(2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen(No.SZSM201812088).
文摘Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined.Here,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient survival.Functionally,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells.CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition.Mechanistically,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT pathway.CCL22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells.The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.
基金This work was supported by the Imported Scholar Project and Startup from Peking University Health Science Center(68263Y1056 to MD).
文摘Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid origin.By binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and cancers.In normal myeloid cells,LILRB4 regulates intrinsic cell activation and differentiation.In disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various diseases.In summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.
