查看更多>>摘要：Once considered unconventional cellular structures,membraneless organelles(MLOs),cellular substructures involved in biological processes or pathways under physiological conditions,have emerged as central players in cellular dynamics and function.MLOs can be formed through liquid-liquid phase separation(LLPS),resulting in the creation of condensates.From neurodegenerative disorders,cardiovascular diseases,aging,and metabolism to cancer,the influence of MLOs on human health and disease extends widely.This review discusses the underlying mechanisms of LLPS,the biophysical properties that drive MLO formation,and their implications for cellular function.We highlight recent advances in understanding how the physicochemical environment,molecular interactions,and post-translational modifications regulate LLPS and MLO dynamics.This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases.This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research,highlighting their critical role in cellular organization.The discussion also covers the role of membrane-associated condensates in cell signaling,including those involving T-cell receptors,stress granules linked to lysosomes,and biomolecular condensates within the Golgi apparatus.Additionally,the potential of targeting LLPS in clinical settings is explored,highlighting promising avenues for future research and therapeutic interventions.
查看更多>>摘要：Epigenetics governs a chromatin state regulatory system through five key mechanisms:DNA modification,histone modification,RNA modification,chromatin remodeling,and non-coding RNA regulation.These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences,playing essential roles in organismal development and homeostasis.Conversely,disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases.This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions.Over the past two decades,a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase,histone deacetylase,isocitrate dehydrogenase,and enhancer of zeste homolog 2,have been thoroughly investigated and implemented as therapeutic options,particularly in oncology.Additionally,numerous epigenetics-targeted drugs are undergoing clinical trials,offering promising prospects for clinical benefits.This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs.These include inhibitors,agonists,degraders,and multitarget agents,aiming to identify practical challenges and promising avenues for future research.Ultimately,this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.
查看更多>>摘要：High efficacy,selectivity and cellular targeting of therapeutic agents has been an active area of investigation for decades.Currently,most clinically approved therapeutics are small molecules or protein/antibody biologics.Targeted action of small molecule drugs remains a challenge in medicine.In addition,many diseases are considered'undruggable'using standard biomacromolecules.Many of these challenges however,can be addressed using nucleic therapeutics.Nucleic acid drugs(NADs)are a new generation of gene-editing modalities characterized by their high efficiency and rapid development,which have become an active research topic in new drug development field.However,many factors,including their low stability,short half-life,high immunogenicity,tissue targeting,cellular uptake,and endosomal escape,hamper the delivery and clinical application of NADs.Scientists have used chemical modification techniques to improve the physicochemical properties of NADs.In contrast,modified NADs typically require carriers to enter target cells and reach specific intracellular locations.Multiple delivery approaches have been developed to effectively improve intracellular delivery and the in vivo bioavailability of NADs.Several NADs have entered the clinical trial recently,and some have been approved for therapeutic use in different fields.This review summarizes NADs development and evolution and introduces NADs classifications and general delivery strategies,highlighting their success in clinical applications.Additionally,this review discusses the limitations and potential future applications of NADs as gene therapy candidates.
查看更多>>摘要：Oncogenic RET alteration is an important,tissue-agnostic therapeutic target across diverse cancers.We conducted a first-in-human phase 1 study on SY-5007,a potent and selective RET inhibitor,in patients with RET-altered solid tumors.Primary endpoints were safety,maximum tolerated dose(MTD),and recommended phase 2 dose(RP2D).Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity.A total of 122 patients were enrolled(17 in dose-escalation phase and 105 in dose-expansion phase),including 91 with non-small cell lung cancer,23 with medullary thyroid cancer,7 with papillary thyroid cancer and 1 with gastric cancer.Treatment-related adverse events(TRAEs)were reported in 96.7％of patients,with the most common grade ≥ 3 TRAEs being hypertension(22.1％),diarrhea(16.4％),hypertriglyceridemia(6.6％),and neutropenia(6.6％).The exposure to SY-5007 was dose proportional.Among the 116 efficacy-evaluable patients,the overall objective response rate(ORR)was 57.8％,with 70.0％in treatment-naive patients and 51.3％in previously treated patients.The median progression-free survival(PFS)was 21.1 months.Efficacy was observed regardless of tumor types and previous therapies.Biomarker analysis of 61 patients with circulating tumor DNA(ctDNA)-detectable RET alterations showed an ORR of 57.4％and median PFS of 13.8 months.Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes.In relapsed patients,off-target induced resistance was observed in 57.1％(12/21),with no on-target RET alterations identified.In conclusion,SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors.Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms(NCT05278364).
查看更多>>摘要：Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to emerge and evade immunity,resulting in breakthrough infections in vaccinated populations.There is an urgent need for the development of vaccines with broad protective effects.In this study,we selected hotspot mutations in the receptor-binding domain(RBD)that contribute to immune escape properties and integrated them into the original RBD protein to obtain a complex RBD protein(cRBD),and we found cRBDs have broad protective effects against SARS-CoV-2 variants.Three cRBDs were designed in our study.Compared with the BA.1 RBD protein,the cRBDs induced the production of higher levels of broader-spectrum neutralizing antibodies,suggesting stronger and broader protective efficacy.In viral challenge experiments,cRBDs were more effective than BA.1 RBD in attenuating lung pathologic injury.Among the three constructs,cRBD3 showed optimal broad-spectrum and protective effects and is a promising candidate for a broad-spectrum SARS-CoV-2 vaccine.In conclusion,immunization with cRBDs triggered immunity against a wide range of variants,including those that emerged after we had completed designing the cRBDs.This study preliminarily explores and validates the feasibility of incorporating hotspot mutations that contribute to immune evasion into the RBD to expand the activity spectrum of antigen-induced antibodies.
查看更多>>摘要：Although first-line immunochemotherapy has improved prognosis for patients with advanced esophageal squamous cell carcinoma(ESCC),more effective strategies still require further investigation.This multi-center,phase Ⅱ study(ClinicalTrials.gov NCT05013697)assessed the feasibility of benmelstobart(a novel PD-L1 inhibitor)plus anlotinib(multitargeted TKI)and chemotherapy in advanced or metastatic/recurrent ESCC.Eligible patients received 4-6 cycles(21-day)of benmelstobart(1200 mg),anlotinib(10 mg)plus paclitaxel(135 mg/m2)/cisplatin(60-75 mg/m2),then maintained with benmelstobart and anlotinib.Primary endpoint was progression-free survival(PFS)assessed according to RECIST v1.1.Secondary endpoints were tumor response,overall survival(OS),and safety assessed by adverse events(AEs).From September 2021 to November 2023,50 patients were enrolled and received study treatment.With median follow-up of 23.7 months as of April 1,2024,median PFS was 14.9 months(95％CI,11.4-not estimable[NE])and the 1-year PFS was 58.5％(95％CI,41.9％-71.9％).Among 50 patients,confirmed objective response rate was 72.0％and disease control rate was 84.0％.Median duration of response of 36 responders was 16.2 months(95％CI,10.2-NE).At the cutoff date,31 patients remained alive;median OS was not reached(95％CI,13.2 months-NE)with 1-year OS of 74.8％(95％Cl,59.8％-84.8％).Forty-six(92.0％)patients reported treatment-related AEs,with 37(74.0％)were grade ≥3.Overall,benmelstobart plus anlotinib and chemotherapy showed promising efficacy and acceptable toxicity in advanced or metastatic/recurrent ESCC.
查看更多>>摘要：Fibroblast activation plays an important role in the occurrence and development of idiopathic pulmonary fibrosis(IPF),which is a progressive,incurable,and fibrotic lung disease.However,the underlying mechanism of fibroblast activation in IPF remains elusive.Here,we showed that the expression levels of STX11 and SNAP25 were downregulated in the lung tissues from patients with IPF and mice with bleomycin(BLM)-induced lung fibrosis as well as in the activated fibroblasts.Upregulation of STX11 or SNAP25 suppressed TGF-β1-induced activation of human lung fibroblasts(HLFs)via promoting autophagy.However,they failed to suppress fibroblast actviation when autophagy was blocked with the use of chloroquine(CQ).In addition,STX11 or SNAP25 could inhibit TGF-β1-induced fibroblast proliferation and migration.In vivo,overexpression of STX11 exerted its protective role in the mice with BLM-induced lung fibrosis.STX11 and SNAP25 mutually promoted expression of each other.Co-IP assay indicated that STX11 has an interaction with SNAP25.Mechanistically,STX11-SNAP25 interaction activated fibroblast autophagy and further inhibited fibroblast activation via blocking the PI3K/AKT/mTOR pathway.Overall,the results suggested that STX11-SNAP25 interaction significantly inhibited lung fibrosis by promoting fibroblast autophagy and suppressing fibroblast activation via blocking the PI3K/ATK/mTOR signaling pathway.Therefore,STX11 serves as a promising therapeutic target in IPF.
查看更多>>摘要：This randomized,prospective,multicenter(12 centers in China)phase Ⅲ trial(Chinese Clinical Trial Registry #ChiCTR2000041170)compared drug-eluting bead transarterial chemoembolization(DEB-TACE)combined with apatinib and DEB-TACE monotherapy for patients with unresectable hepatocellular carcinoma(uHCC).Progression-free survival(PFS)was the primary endpoint.Overall survival(OS),mRECIST-based objective response rates(ORR)and disease control rates(DCR),and treatment-related adverse events(TRAEs)were secondary endpoints.Totally 243 cases were randomized,with 122 and 121 in the DEB-TACE+apatinib and DEB-TACE groups,respectively.Cases administered DEB-TACE+apatinib displayed markedly improved median PFS(7.1 months[95％CI 6.6-8.3]vs.5.2 months[95％CI 5.0-5.9])and OS(23.3 months[95％CI 20.7-29.6]vs.18.9 months[95％CI 17.9-20.1]compared with those treated with DEB-TACE(both p＜0.001).Additionally,patients administered DEB-TACE+apatinib had elevated ORR(56.6％vs.38.8％)and DCR(89.3％vs.80.2％)versus the DEB-TACE group(both p＜0.001).Majority of TRAEs were mild and manageable.Regarding DEB-TACE-related TRAEs,the rates of hepatic artery thinning and spasms were elevated during the second DEB-TACE in cases administered DEB-TACE+apatinib vs.DEB-TACE.The commonest apatinib-related TRAEs in the DEB-TACE+apatinib group included hypertension,hand-foot syndrome,fatigue,and diarrhea.In conclusion,DEB-TACE plus apatinib demonstrates superior PFS versus DEB-TACE monotherapy in uHCC cases,maintaining a favorable safety profile with similar occurrences of AEs.
查看更多>>摘要：Current therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness.To address this limitation,our focus was on CD132,a subunit common to six inflammatory factor receptors implicated in SLE.Our study revealed heightened CD132 expression in SLE patients'lymphocytes,contributing to the production of pro-inflammatory cytokines and immunoglobulins.We developed a novel humanized anti-CD132 monoclonal antibody,named as 2D4.2D4 efficiently blocked IL-21 and IL-15,with limited effectiveness against IL-2,thereby suppressing T and B cells without disrupting immune tolerance.In the mouse immunization model,2D4 virtually inhibited T cell-dependent,antigen-specific B-cell response.In lupus murine models,2D4 mitigated inflammation by suppressing multiple pro-inflammatory cytokines and anti-dsDNA antibody titers,also diminishing proteinuria and glomerulonephritis.Compared to Belimumab,2D4 exhibited superior efficacy in ameliorating the inflammatory state and preserving renal function.Moreover,2D4 exhibited the ability to inhibit the production of pro-inflammatory factors and autoantibodies in PBMCs from individuals with SLE,highlighting its therapeutic potential for SLE individuals.Potent,2D4 has the potential to significantly improve clinical outcomes in SLE and other complex autoimmune disorders.
查看更多>>摘要：The heterogeneity of Parkinson's disease(PD)has been recognized in clinical,with patients categorized into distinct subsets based on motor phenotype,such as tremor-dominant PD(TD),postural instability and gait difficulty-dominant PD(PIGD)and mixed PD(Mix).Despite this categorization,the underlying mechanisms of this heterogeneity remain poorly understood,and there is no personalized effective treatment for each PD subtype.To address this,a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA,followed by cluster analysis of behavioral data.The serum neurofilament light chain(NfL)and uric acid(UA)levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients,and metabolomics results showed that more than 70％of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered.Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter,neuronal damage in the central or peripheral nervous system,and lipid metabolism.In addition,based on the subtype-specific differentially expressed genes,25 potential drug candidates were identified.Notably,the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats,highlighting the possibility of selecting targeted treatments for well-defined individuals.
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