BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-d...BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.展开更多
Hydrogen peroxide(H2 O2), as important products of oxygen metabolism, plays an important role in many biological processes, such as immune responses and cellular signal transduction. However, abnormal production of H2...Hydrogen peroxide(H2 O2), as important products of oxygen metabolism, plays an important role in many biological processes, such as immune responses and cellular signal transduction. However, abnormal production of H2 O2 can damage cellular biomolecules, which was closely associated with many diseases.Thus, it is urgent to monitor the level change of H2 O2 in living cells, particularly at subcellular levels.Toward this end, a wide variety of H2 O2 fluorescent probes have been designed, developed and applied for imaging of H2 O2 in subcellular levels. In this review, we highlight the representative cases of H2 O2 fluorescent probes with mitochondria, nuclei and lysosomes-targetable ability. The review contains organelle target strategies, structures, fluorescence behavior and biological applications of these probes.展开更多
Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine i...Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC.展开更多
Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems unde...Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems undertakes critical responsibility.Herein,we have developed a novel two-photon fluorescence turn on probe,named as Pyp-B for mitochondria H2O2 detection in living systems.Selectivity studies show that probe Pyp-B exhibit highly sensitive response toward H2O2 than other reactive oxygen species(ROS)and reactive nitrogen species(RNS)as well as biologically relevant species.The fluorescence colocalization studies demonstrate that the probe can localize in the mitochondria solely.Furthermore,as a bio-compatibility molecule,the highly selective and sensitive of fluorescence probe Pyp-B have been confirmed by its cell imaging application of H2O2 in living A549 cells and zebrafishes under the physiological conditions.展开更多
Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Dr...Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].展开更多
Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathologica...Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathological characteristics and molecular pathways associated with its progression.Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease.These non-coding RNAs regulate several biological processes critical to the advancement of the disease,offering promising potential as therapeutic targets and diagnostic biomarkers.Therefore,this review aims to investigate the underlying mechanisms of Alzheimer's disease onset,with a particular focus on microRNAs,long non-coding RNAs,and circular RNAs associated with the disease.The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs.It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease,as well as how these noncoding RNAs influence the disease's progression by regulating gene expression and protein functions.For example,miR-9 targets the UBE4B gene,promoting autophagy-mediated degradation of Tau protein,thereby reducing Tau accumulation and delaying Alzheimer's disease progression.Conversely,the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA,promoting the generation of amyloid-βand accelerating Alzheimer's disease development.Additionally,circular RNAs play significant roles in regulating neuroinflammatory responses.By integrating insights from these regulatory mechanisms,there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease.This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs,potentially paving the way for early detection and novel treatment strategies.展开更多
The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of th...The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.展开更多
Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of ...Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of life and restrict therapeutic outcomes.Addressing this pressing issue,this review presents a thorough and systematic analysis of innovative and emerging strategies designed to minimize the toxicity induced by treatment,while maintaining or even enhancing antitumor efficacy.The focus is on six promising therapeutic approaches:combination therapies utilizing natural bioactive products,molecularly targeted therapies,immunotherapies,nanotechnology-mediated drug delivery systems,adjunct traditional Chinese medicine interventions,and low-dose spatiotemporally concerted regimens.Each approach employs unique mechanisms—such as enhanced targeting precision,immune system activation,tumor microenvironment reprogramming,and multi-component synergistic effects—to mitigate damage to normal tissues and reduce systemic adverse reactions.Despite promising preclinical and clinical advancements,several challenges persist,including drug resistance,high economic costs,a lack of reliable predictive biomarkers,and complexities in clinical translation and regulatory approval.Looking ahead,the incorporation of artificial intelligence,multi-omics profiling,and novel biomimetic nanotechnologies offers unprecedented opportunities for developing highly personalized,low-toxicity treatment frameworks.This review highlights a fundamental shift in oncology towards precision medicine that balances efficacy with safety,demonstrating the transformative potential of these strategies in shaping the future of cancer therapy and enhancing patient care globally.展开更多
This paper solves the problem of model-free dual-arm space robot maneuvering after non-cooperative target capture under high control quality requirements.The explicit system model is unavailable,and the maneuvering mi...This paper solves the problem of model-free dual-arm space robot maneuvering after non-cooperative target capture under high control quality requirements.The explicit system model is unavailable,and the maneuvering mission is disturbed by the measurement noise and the target adversarial behavior.To address these problems,a model-free Combined Adaptive-length Datadriven Predictive Controller(CADPC)is proposed.It consists of a separated subsystem identification method and a combined predictive control strategy.The subsystem identification method is composed of an adaptive data length,thereby reducing sensitivity to undetermined measurement noises and disturbances.Based on the subsystem identification,the combined predictive controller is established,reducing calculating resource.The stability of the CADPC is rigorously proven using the Input-to-State Stable(ISS)theorem and the small-gain theorem.Simulations demonstrate that CADPC effectively handles the model-free space robot post operation in the presence of significant disturbances,state measurement noise,and control input errors.It achieves improved steady-state accuracy,reduced steady-state control consumption,and minimized control input chattering.展开更多
Age-related macular degeneration(AMD)is the leading cause of irreversible vision loss in older adults,with early-stage features including subretinal lipid deposits and progressing to retinal geographic atrophy and cho...Age-related macular degeneration(AMD)is the leading cause of irreversible vision loss in older adults,with early-stage features including subretinal lipid deposits and progressing to retinal geographic atrophy and choroidal neovascularization in advanced stages.The dysregulation of ocular lipid metabolism,oxidative stress,and inflammation are critical risk factors for AMD pathogenesis.7-ketocholesterol(7-KC),a hallmark of ocular lipid metabolism disorders,is a significant component of subretinal lipid deposits in AMD patients,exhibiting toxicity to retinal cells and exacerbating lipotoxic aging.This review elaborates on the biosynthesis and metabolism of 7-KC in the retina,investigates its detoxification mechanisms by examining its binding proteins,and summarizes recent progress on kinase signaling pathways induced by 7-KC through inflammatory cytokines and intracellular effectors.The aim is to pinpoint potential pharmacological targets,nutritional compounds,and synthetic molecules to explore the potential of targeting 7-KC for AMD treatment.展开更多
A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an or...A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an orally administered nanogene delivery system.Designed to achieve in situ,efficient delivery of chimeric antigen receptor(CAR)genes to tumor sites,this approach offers a novel strategy for CAR-macrophage(CAR-M)based immunotherapy.Its key highlights are as follows.展开更多
Measuring cross sections of nuclear reactions,such as the so-called“Holy Grail”reaction,^(12)C(σ,γ)^(16)O,is essential for understanding stellar nucleosynthesis but presents significant challenges due to extremely...Measuring cross sections of nuclear reactions,such as the so-called“Holy Grail”reaction,^(12)C(σ,γ)^(16)O,is essential for understanding stellar nucleosynthesis but presents significant challenges due to extremely low cross sections.Key challenges include significant energy loss as ions penetrate the target material,limiting measurements to thin target layers.To overcome these obstacles,we propose a novel method,the in-target energy loss compensating(eLOC)method,specifically designed for gas targets,which utilizes a gas-filled magnetic field and accelerating electric fields to compensate for ion energy loss in the target.Simulations show that this approach significantly enhances the effective target thickness by over 140 times in the case of the“Holy Grail”reaction with an inverse-kinematics setup.This eLOC method may provide a powerful new tool for obtaining critical data in nuclear astrophysics,thereby advancing our understanding of stellar nucleosynthesis and the origins of elements in the universe,as well as benefiting other related fields such as isotope production.展开更多
Considering the impact of terminal impact time constraints and the state information of maneuvering targets on the guidance accuracy in multi-UAV cooperative guidance,this paper proposes an impact time cooperative con...Considering the impact of terminal impact time constraints and the state information of maneuvering targets on the guidance accuracy in multi-UAV cooperative guidance,this paper proposes an impact time cooperative control guidance law(ITCCG)that combines the optimal error dynamics with an improved adaptive cubature Kalman filter(IACKF)algorithm.First,a terminal impact time feedback term is introduced into proportional navigation guidance based on the relative virtual guidance model,and terminal time control is achieved through optimal error dynamics.Then,the Huber loss function is used to reduce the impact of measurement outliers,and the diagonal decomposition is applied to address the issue of non-positive definite matrices that cannot undergo Cholesky decomposition.Finally,the ITCCG and IACKF algorithms combined achieve multi-UAV time-cooperated guidance based on maneuvering target state estimation.Simulation results show that the proposed algorithm effectively reduces the target state estimation error and achieves cooperative guidance within the desired time frame.展开更多
Adolescent smoking constitutes a critical public health challenge as early initiation increases the risk of premature mortality and smoking-related chronic diseases due to longer exposure and higher cumulative tobacco...Adolescent smoking constitutes a critical public health challenge as early initiation increases the risk of premature mortality and smoking-related chronic diseases due to longer exposure and higher cumulative tobacco use^([1]).Adolescents are especially prone to developing persistent smoking habits,with many adult smokers having started before the age of 18.In China,16.7%of secondary school students have tried smoking and 4.7%are current smokers,highlighting the critical need for targeted tobacco control interventions among the youth.展开更多
Hebei Province has incorporated targeted assistance services for people with disabilities into livelihood projects,upgrading the quality and efficiency of support services for disadvantaged groups.THE living and nursi...Hebei Province has incorporated targeted assistance services for people with disabilities into livelihood projects,upgrading the quality and efficiency of support services for disadvantaged groups.THE living and nursing allowances provided by the Chinese government for people with disabilities who are unable to work are not only important components of China’s social security system which provide for the needs of its disabled,but also show China’s ability to guarantee the basic living standard and social fairness and justice for this group of people.展开更多
The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integrat...The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies.Human epidermal growth factor receptor,hormone receptors,and angiogenesis factors are among the established therapies in tumor reduction and managing side effects.Novel targeted therapies like KRAS G12C,Claudin-18 isoform 2(CLDN18.2),Trophoblast cell-surface antigen 2(TROP2),and epigenetic regulators emphasize their promise in advancing precision medicine.However,in many cases,the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions.The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology.This review seeks to elucidate recent advancements,address persisting challenges,and explore opportunities for innovative developments in cancer target research.Additionally,it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research.In conclusion,innovative approaches in oncology,supported by pharmacological research,ongoing clinical trials,molecular biosciences,and artificial intelligence,are poised to significantly transform cancer treatment.展开更多
Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understo...Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.展开更多
Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic i...Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.展开更多
Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, ...Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.展开更多
Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen re...Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells.Herein,we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group.Compared to previously reported pyridone-based monofunctional endoperoxides,the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.展开更多
文摘BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
基金the National Natural Science Foundation of China (Nos. 21705102, 21775096)the Shanxi Province Science Foundation for Youths (No. 201701D221061)+1 种基金Shanxi Province Foundation for Returnees (No. 2017-026)Scientific Instrument Center of Shanxi University (No. 201512)
文摘Hydrogen peroxide(H2 O2), as important products of oxygen metabolism, plays an important role in many biological processes, such as immune responses and cellular signal transduction. However, abnormal production of H2 O2 can damage cellular biomolecules, which was closely associated with many diseases.Thus, it is urgent to monitor the level change of H2 O2 in living cells, particularly at subcellular levels.Toward this end, a wide variety of H2 O2 fluorescent probes have been designed, developed and applied for imaging of H2 O2 in subcellular levels. In this review, we highlight the representative cases of H2 O2 fluorescent probes with mitochondria, nuclei and lysosomes-targetable ability. The review contains organelle target strategies, structures, fluorescence behavior and biological applications of these probes.
文摘Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC.
基金the financial support from the National Natural Science Foundation of China(No.81860630)the China Postdoctoral Science Foundation(No.2019M662968)GuangdongBasic and Applied Basic Research Foundation(Nos.2019A1515110356,2019A1515110877)。
文摘Considering that hydrogen peroxide(H2O2)plays significant roles in oxidative stress,the cellular signal transduction and essential biological process regulation,the detection and imaging of H2O2 in living systems undertakes critical responsibility.Herein,we have developed a novel two-photon fluorescence turn on probe,named as Pyp-B for mitochondria H2O2 detection in living systems.Selectivity studies show that probe Pyp-B exhibit highly sensitive response toward H2O2 than other reactive oxygen species(ROS)and reactive nitrogen species(RNS)as well as biologically relevant species.The fluorescence colocalization studies demonstrate that the probe can localize in the mitochondria solely.Furthermore,as a bio-compatibility molecule,the highly selective and sensitive of fluorescence probe Pyp-B have been confirmed by its cell imaging application of H2O2 in living A549 cells and zebrafishes under the physiological conditions.
基金supported by a grant from the SMARCB1 associationsupported by grants from the Dr.Rolf M.Schwiete foundation(2021-007,2022-031)+11 种基金the Matthias-Lackas foundationthe Dr.Leopold und Carmen Ellinger foundationthe Deutsche Forschungsgemeinschaft(DFG 458891500)the Cancer Grand Challenges project PROTECTthe German Cancer Aid(DKH-7011411,DKH-70114278,DKH-70115315,DKH-70115914)the Ministry of Education and Research(BMBF,SMART-CARE and HEROES-AYA)the KiKa foundation(#486)the Fight Kids Cancer foundation(FKC-NEWtargets)the KiTZ-Foundation in memory of Kirstin Diehl,the KiTZPMC twinning programthe German Cancer Consortium(DKTK,PRedictAHR)the Barbara and Wilfried Mohr foundationThe laboratory of Thomas G.P.Grünewald is co-funded by the European Union(ERC,CANCERHARAKIRI,101122595).
文摘Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].
文摘Alzheimer's disease,a progressively degenerative neurological disorder,is the most common cause of dementia in the elderly.While its precise etiology remains unclear,researchers have identified diverse pathological characteristics and molecular pathways associated with its progression.Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease.These non-coding RNAs regulate several biological processes critical to the advancement of the disease,offering promising potential as therapeutic targets and diagnostic biomarkers.Therefore,this review aims to investigate the underlying mechanisms of Alzheimer's disease onset,with a particular focus on microRNAs,long non-coding RNAs,and circular RNAs associated with the disease.The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs.It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease,as well as how these noncoding RNAs influence the disease's progression by regulating gene expression and protein functions.For example,miR-9 targets the UBE4B gene,promoting autophagy-mediated degradation of Tau protein,thereby reducing Tau accumulation and delaying Alzheimer's disease progression.Conversely,the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA,promoting the generation of amyloid-βand accelerating Alzheimer's disease development.Additionally,circular RNAs play significant roles in regulating neuroinflammatory responses.By integrating insights from these regulatory mechanisms,there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease.This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs,potentially paving the way for early detection and novel treatment strategies.
基金partly supported by the Yan’an University Qin Chuanyuan“Scientist+Engineer”Team Special Fund,No.2023KXJ-012(to YL)Yan’an University Transformation of Scientific and Technological Achievements Fund,No.2023CGZH-001(to YL)+2 种基金College Students Innovation and Entrepreneurship Training Program,Nos.D2023158,202410719056(to XS,JM)Yan’an University Production and Cultivation Project,No.CXY202001(to YL)Kweichow Moutai Hospital Research and Talent Development Fund Project,No.MTyk2022-25(to XO)。
文摘The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
文摘Cancer continues to pose a formidable challenge in global health,with conventional treatments such as chemotherapy and radiotherapy often resulting in severe toxicities that significantly degrade patients’quality of life and restrict therapeutic outcomes.Addressing this pressing issue,this review presents a thorough and systematic analysis of innovative and emerging strategies designed to minimize the toxicity induced by treatment,while maintaining or even enhancing antitumor efficacy.The focus is on six promising therapeutic approaches:combination therapies utilizing natural bioactive products,molecularly targeted therapies,immunotherapies,nanotechnology-mediated drug delivery systems,adjunct traditional Chinese medicine interventions,and low-dose spatiotemporally concerted regimens.Each approach employs unique mechanisms—such as enhanced targeting precision,immune system activation,tumor microenvironment reprogramming,and multi-component synergistic effects—to mitigate damage to normal tissues and reduce systemic adverse reactions.Despite promising preclinical and clinical advancements,several challenges persist,including drug resistance,high economic costs,a lack of reliable predictive biomarkers,and complexities in clinical translation and regulatory approval.Looking ahead,the incorporation of artificial intelligence,multi-omics profiling,and novel biomimetic nanotechnologies offers unprecedented opportunities for developing highly personalized,low-toxicity treatment frameworks.This review highlights a fundamental shift in oncology towards precision medicine that balances efficacy with safety,demonstrating the transformative potential of these strategies in shaping the future of cancer therapy and enhancing patient care globally.
基金supported by the National Natural Science Foundation of China(No.12372045)the National Key Research and the Development Program of China(Nos.2023YFC2205900,2023YFC2205901)。
文摘This paper solves the problem of model-free dual-arm space robot maneuvering after non-cooperative target capture under high control quality requirements.The explicit system model is unavailable,and the maneuvering mission is disturbed by the measurement noise and the target adversarial behavior.To address these problems,a model-free Combined Adaptive-length Datadriven Predictive Controller(CADPC)is proposed.It consists of a separated subsystem identification method and a combined predictive control strategy.The subsystem identification method is composed of an adaptive data length,thereby reducing sensitivity to undetermined measurement noises and disturbances.Based on the subsystem identification,the combined predictive controller is established,reducing calculating resource.The stability of the CADPC is rigorously proven using the Input-to-State Stable(ISS)theorem and the small-gain theorem.Simulations demonstrate that CADPC effectively handles the model-free space robot post operation in the presence of significant disturbances,state measurement noise,and control input errors.It achieves improved steady-state accuracy,reduced steady-state control consumption,and minimized control input chattering.
文摘Age-related macular degeneration(AMD)is the leading cause of irreversible vision loss in older adults,with early-stage features including subretinal lipid deposits and progressing to retinal geographic atrophy and choroidal neovascularization in advanced stages.The dysregulation of ocular lipid metabolism,oxidative stress,and inflammation are critical risk factors for AMD pathogenesis.7-ketocholesterol(7-KC),a hallmark of ocular lipid metabolism disorders,is a significant component of subretinal lipid deposits in AMD patients,exhibiting toxicity to retinal cells and exacerbating lipotoxic aging.This review elaborates on the biosynthesis and metabolism of 7-KC in the retina,investigates its detoxification mechanisms by examining its binding proteins,and summarizes recent progress on kinase signaling pathways induced by 7-KC through inflammatory cytokines and intracellular effectors.The aim is to pinpoint potential pharmacological targets,nutritional compounds,and synthetic molecules to explore the potential of targeting 7-KC for AMD treatment.
文摘A recently published study(Xin et al.,Prog Biochem Biophys,2026,53(2):431-441.DOI:10.3724/j.pibb.2025.0508)addresses the therapeutic challenges of pancreatic ductal adenocarcinoma(PDAC)by innovatively developing an orally administered nanogene delivery system.Designed to achieve in situ,efficient delivery of chimeric antigen receptor(CAR)genes to tumor sites,this approach offers a novel strategy for CAR-macrophage(CAR-M)based immunotherapy.Its key highlights are as follows.
基金supported by the the National Key R&D Program of China (Grant Nos.2023YFA1606900 and 2022YFA1602301)the National Natural Science Foundation of China (Grant Nos.12235003,12435010,and 12147101)+3 种基金the Guangdong Major Project of Basic and Applied Basic Research (Grant No.2020B0301030008)the STCSM (Grant No.23590780100)the Natural Science Foundation of Shanghai (Grant No.23JC1400200)the China Postdoctoral Science Foundation (Grant No.2024M760483)。
文摘Measuring cross sections of nuclear reactions,such as the so-called“Holy Grail”reaction,^(12)C(σ,γ)^(16)O,is essential for understanding stellar nucleosynthesis but presents significant challenges due to extremely low cross sections.Key challenges include significant energy loss as ions penetrate the target material,limiting measurements to thin target layers.To overcome these obstacles,we propose a novel method,the in-target energy loss compensating(eLOC)method,specifically designed for gas targets,which utilizes a gas-filled magnetic field and accelerating electric fields to compensate for ion energy loss in the target.Simulations show that this approach significantly enhances the effective target thickness by over 140 times in the case of the“Holy Grail”reaction with an inverse-kinematics setup.This eLOC method may provide a powerful new tool for obtaining critical data in nuclear astrophysics,thereby advancing our understanding of stellar nucleosynthesis and the origins of elements in the universe,as well as benefiting other related fields such as isotope production.
基金supported by the Fundamental Research Funds for the Central Universities of China(FRF-TP-24-058A)with additional support from the National Key Laboratory of Helicopter Aeromechanics(2024-ZSJ-LB-02-02).
文摘Considering the impact of terminal impact time constraints and the state information of maneuvering targets on the guidance accuracy in multi-UAV cooperative guidance,this paper proposes an impact time cooperative control guidance law(ITCCG)that combines the optimal error dynamics with an improved adaptive cubature Kalman filter(IACKF)algorithm.First,a terminal impact time feedback term is introduced into proportional navigation guidance based on the relative virtual guidance model,and terminal time control is achieved through optimal error dynamics.Then,the Huber loss function is used to reduce the impact of measurement outliers,and the diagonal decomposition is applied to address the issue of non-positive definite matrices that cannot undergo Cholesky decomposition.Finally,the ITCCG and IACKF algorithms combined achieve multi-UAV time-cooperated guidance based on maneuvering target state estimation.Simulation results show that the proposed algorithm effectively reduces the target state estimation error and achieves cooperative guidance within the desired time frame.
基金supported by the World Health Organization Global Youth Tobacco Survey(WPDHP1206671)the Global Health Capacity Building and Tobacco Control Project:Tobacco Epidemic Monitoring and Comprehensive Tobacco Control Intervention。
文摘Adolescent smoking constitutes a critical public health challenge as early initiation increases the risk of premature mortality and smoking-related chronic diseases due to longer exposure and higher cumulative tobacco use^([1]).Adolescents are especially prone to developing persistent smoking habits,with many adult smokers having started before the age of 18.In China,16.7%of secondary school students have tried smoking and 4.7%are current smokers,highlighting the critical need for targeted tobacco control interventions among the youth.
文摘Hebei Province has incorporated targeted assistance services for people with disabilities into livelihood projects,upgrading the quality and efficiency of support services for disadvantaged groups.THE living and nursing allowances provided by the Chinese government for people with disabilities who are unable to work are not only important components of China’s social security system which provide for the needs of its disabled,but also show China’s ability to guarantee the basic living standard and social fairness and justice for this group of people.
文摘The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy.Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies.Human epidermal growth factor receptor,hormone receptors,and angiogenesis factors are among the established therapies in tumor reduction and managing side effects.Novel targeted therapies like KRAS G12C,Claudin-18 isoform 2(CLDN18.2),Trophoblast cell-surface antigen 2(TROP2),and epigenetic regulators emphasize their promise in advancing precision medicine.However,in many cases,the resistance mechanisms associated with these interventions render them ineffective in carrying out their functions.The purpose of this review is to provide a comprehensive and up-to-date examination of both established and emerging drug targets and mechanisms of treatment resistance in oncology.This review seeks to elucidate recent advancements,address persisting challenges,and explore opportunities for innovative developments in cancer target research.Additionally,it explores the growing role of artificial intelligence in reshaping cancer drug discovery and development frameworks as potential avenues for future research.In conclusion,innovative approaches in oncology,supported by pharmacological research,ongoing clinical trials,molecular biosciences,and artificial intelligence,are poised to significantly transform cancer treatment.
文摘Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.
基金supported in part by the National Natural Science Foundation of China,Nos.81927804(to GL),82260456(to LY),U21A20479(to LY)Science and Technology Planning Project of Shenzhen,No.JCYJ20230807140559047(to LY)+3 种基金Key-Area Research and Development Program of Guangdong Province,No.2020B0909020004(to GL)Guangdong Basic and Applied Research Foundation,No.2023A1515011478(to LY)the Science and Technology Program of Guangdong Province,No.2022A0505090007(to GL)Ministry of Science and Technology,Shenzhen,No.QN2022032013L(to LY)。
文摘Neural machine interface technology is a pioneering approach that aims to address the complex challenges of neurological dysfunctions and disabilities resulting from conditions such as congenital disorders,traumatic injuries,and neurological diseases.Neural machine interface technology establishes direct connections with the brain or peripheral nervous system to restore impaired motor,sensory,and cognitive functions,significantly improving patients'quality of life.This review analyzes the chronological development and integration of various neural machine interface technologies,including regenerative peripheral nerve interfaces,targeted muscle and sensory reinnervation,agonist–antagonist myoneural interfaces,and brain–machine interfaces.Recent advancements in flexible electronics and bioengineering have led to the development of more biocompatible and highresolution electrodes,which enhance the performance and longevity of neural machine interface technology.However,significant challenges remain,such as signal interference,fibrous tissue encapsulation,and the need for precise anatomical localization and reconstruction.The integration of advanced signal processing algorithms,particularly those utilizing artificial intelligence and machine learning,has the potential to improve the accuracy and reliability of neural signal interpretation,which will make neural machine interface technologies more intuitive and effective.These technologies have broad,impactful clinical applications,ranging from motor restoration and sensory feedback in prosthetics to neurological disorder treatment and neurorehabilitation.This review suggests that multidisciplinary collaboration will play a critical role in advancing neural machine interface technologies by combining insights from biomedical engineering,clinical surgery,and neuroengineering to develop more sophisticated and reliable interfaces.By addressing existing limitations and exploring new technological frontiers,neural machine interface technologies have the potential to revolutionize neuroprosthetics and neurorehabilitation,promising enhanced mobility,independence,and quality of life for individuals with neurological impairments.By leveraging detailed anatomical knowledge and integrating cutting-edge neuroengineering principles,researchers and clinicians can push the boundaries of what is possible and create increasingly sophisticated and long-lasting prosthetic devices that provide sustained benefits for users.
文摘Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.
基金supported by the National Natural Science Foundation of China(22007008,22178048).
文摘Naphthalene,anthracene and pyridone endoperoxides are known to thermally release singlet oxygen.However,in the cycloreversion reaction,singlet oxygen is produced stoichiometrically;therefore,multiple singlet oxygen releasing modules are expected to be very useful in inducing apoptosis of cancer cells.Herein,we present a potential therapeutic agent presenting three-pyridone endoperoxide modules and a mitochondria targeting group.Compared to previously reported pyridone-based monofunctional endoperoxides,the triple endoperoxide is highly effective as evidenced by assays and fluorescence microscopy.
