Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,ven...Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,venetoclax plus azacitidine(VEN-AZA)or intensive chemotherapy(IC)]on post-transplant outcomes remains inconclusive.This multicenter,retrospective study compared the post-transplant outcomes between patients receiving VEN-AZA and those receiving IC before allo-HSCT.Methods:This study was based on the transplant database of TROPHY group.Consecutive adverse-risk AML patients receiving allo-HSCT from January 2021 to June 2023 were screened in five Chinese transplant centers.Patients were categorized into VEN-AZA group if they received venetoclax combined with azacitidine as first-line therapy followed by allo-HSCT.Patients who received first-line therapy consisting of a mainstay treatment of cytarabine and anthracycline followed by allo-HSCT were categorized into IC group.Results:In the total cohort,the 3-year probabilities of overall survival,leukemia-free survival,and event-free survival were better in the IC group than VEN-AZA group,particularly for patients with ASXL1 mutations or SF3B1 mutations.However,the survival of the VEN-AZA group was not superior to that of IC group in patients aged≥55 years or those with the hematopoietic cell transplantation-comorbidity index scores≥1 before allo-HSCT.After propensity score matching(median age:VEN-AZA group:57 years;IC group:55 years),only the probability of overall survival for the IC group was better than that of VEN-AZA group(93.6%vs.78.0%,P=0.034)at the 1-year follow-up;however,all of the other clinical outcomes were comparable between the VEN-AZA and IC groups.The TP53 mutation was independently associated with post-transplant relapse and survival.Conclusions:Our results suggest that IC remains the cornerstone of therapy,whereas VEN-AZA may also be used in younger patients and medically fit patients with adverse-risk AML who are receiving allo-HSCT in CR1.展开更多
Remodeling plant intracellular nucleotide-binding leucine-rich repeat immune receptors(NLRs)to engineer synthetic disease-resistance genes has emerged as a promising approach to achieving broad-spectrum disease resist...Remodeling plant intracellular nucleotide-binding leucine-rich repeat immune receptors(NLRs)to engineer synthetic disease-resistance genes has emerged as a promising approach to achieving broad-spectrum disease resistance.But strategies for expanding NLR recognition spectra[[1],[2],[3],[4],[5]]are often limited by the rapid evolution of pathogens and pests.In our recent study,we developed an innovative strategy to engineer broad-spectrum,durable and complete disease resistance in plants by remodeling autoactive NLRs into protease-activated switches[6].展开更多
Since 1968 when the first successful hematopoietic stem cell transplantation(HSCT) was performed, transplant technique has developed rapidly for more than 50 years. In the past 20 years, the significant breakthroughs ...Since 1968 when the first successful hematopoietic stem cell transplantation(HSCT) was performed, transplant technique has developed rapidly for more than 50 years. In the past 20 years, the significant breakthroughs and widely use of haploidentical-related donor HSCT(e.g. Beijing Protocol) make everyone can have a donor(1), and the novel, reduced-toxicity transplant regimens help elderly patients receive HSCT safely(2).展开更多
Stretchability is a crucial property of flexible all-in-one supercapacitors.This work reports a novel hydrogel electrolyte,polyacrylamidedivinylbenzene-Li2SO4(PAM-DVB-Li)synthesized by using a strategy of combining hy...Stretchability is a crucial property of flexible all-in-one supercapacitors.This work reports a novel hydrogel electrolyte,polyacrylamidedivinylbenzene-Li2SO4(PAM-DVB-Li)synthesized by using a strategy of combining hydrophobic nodes and hydrophilic networks as well as a method of dispersing hydrophobic DVB crosslinker to acrylamide monomer/Li2SO4 aqueous solution by micelles and followedγ-radiation induced polymerization and crosslinking.The resultant PAM-DVB-Li hydrogel electrolyte possesses excellent mechanical properties with 5627±241%stretchability and high ionic conductivity of 53±3 mS cm^(-1).By in situ polymerization of conducting polyaniline(PANI)on the PAM-DVB-Li hydrogel electrolyte,a novel all-in-one supercapacitor,PAM-DVB-Li/PANI,with highly integrated structure is prepared further.Benefiting from the excellent properties of hydrogel electrolyte and the all-in-one structure,the device exhibits a high specific capacitance of 469 mF cm^(-2) at 0.5 mA cm^(-2),good cyclic stability,safety,and deformation damage resistance.More importantly,the device demonstrates a superior tensile resistance(working normally under no more than 300%strain,capacitance stability in 1000 cycles of 1000%stretching and 10 cycles of 3000%stretching)far beyond that of other all-in-one supercapacitors.This work proposes a novel strategy to construct tensile-resistant all-in-one flexible supercapacitors that can be used as an energy storage device for stretchable electronic devices.展开更多
Alzheimer’s disease(AD)is a degenerative disease of the central nervous system.It results in cognitive dysfunction due to the loss of functional neurons and a deficit of new neurons,which can lead to death in severe ...Alzheimer’s disease(AD)is a degenerative disease of the central nervous system.It results in cognitive dysfunction due to the loss of functional neurons and a deficit of new neurons,which can lead to death in severe cases.Repairing damaged neurons by promoting hippocampal neurogenesis has become therapeutic modality to combat neurodegenerative diseases.The novel isoflavone alkaloid LY01,found in the edible fruits of Sophora alopecuroides L.,has various neuroprotective effects.However,the molecular mechanism by which it promotes the proliferation of endogenous neural stem cells(NSCs)is not yet precisely known.The effects of LY01 were investigated in vivo and in vitro.In vivo experiments showed that LY01 could counteract the toxic damage of amyloid β-protein(Aβ),enhance the learning ability and memory capacity of 5×FAD mice,and improve the morphology of neurons in the hippocampal region.In vitro experiments showed that LY01 was effective against antioxidant damage,improved the cell morphology of C17.2 mouse NSCs after hydrogen peroxide injury,and increased cell viability.Both in vitro and in vivo experiments promoted NSC proliferation by upregulating the mRNA and protein levels of the critical genes of the Wnt/β-catenin pathway,which increased levels of doublecortin to facilitate new neuronal generation.This indicates that the ability of LY01 to counteract Aβ toxicity and alleviate oxidative damage in early AD is associated with activation of the Wnt/β-catenin signaling pathway to promote NSC proliferation and thus repair damaged neurons.展开更多
Objective:Immune effector cell-associated hematotoxicity(ICAHT),characterized by prolonged cytopenia and delayed hematopoietic recovery,is a common complication following chimeric antigen receptor T(CAR-T)cell therapy...Objective:Immune effector cell-associated hematotoxicity(ICAHT),characterized by prolonged cytopenia and delayed hematopoietic recovery,is a common complication following chimeric antigen receptor T(CAR-T)cell therapy.However,the applicability of existing predictive models,CAR-HEMATOTOX(CAR-HT)for lymphoma,acute lymphoblastic leukemia-HEMATOTOX(ALL-HT)for B-ALL,and the early ICAHT prediction model(e IPM),remains uncertain across different hematologic malignancies.Methods:We prospectively analyzed 119 patients who received CAR-T therapy between January 2022 and June2025,including B-ALL(n=62),T-ALL/non-Hodgkin's lymphoma(NHL)(n=25),and multiple myeloma(MM,n=32).The CAR-HT,ALL-HT,and e IPM models were evaluated for their ability to predict ICAHT severity and survival outcomes.Results:Grade 3 ICAHT occurred in 32.3%of B-ALL,40.0%of T-ALL/NHL,and 25.0%of MM patients,while grade 4 rates were 33.9%,20.0%,and 6.3%,respectively.CAR-HT classified 67.2%of patients as high-risk,and ALL-HT identified 56.3%of ALL/NHL patients as high-risk.In both models,high-risk groups experienced significantly more prolonged neutropenia than low-risk groups(CAR-HT:17.7 vs.5.3 d,P<0.001;ALL-HT:21.3 vs.7.7 d,P<0.001).Both e IPMpre and e IPMpost strongly correlated with grade 3-4 ICAHT(P<0.001).Importantly,survival analysis showed that e IPMpre stratification distinguished outcomes:1-year overall survival(OS)was 65%in medium+high-risk vs.84%in low-risk patients(P=0.006),and 1-year disease-free survival(DFS)was 44%vs.73%(P<0.001).Similar predictive accuracy was observed with e IPMpost.Conclusions:The CAR-HT,ALL-HT,and e IPM models consistently identify patients at high risk for severe ICAHT across B-ALL,T-ALL/NHL,and MM.Among these,the e IPM stands out as a promising universal tool for survival prediction.These models provide valuable prognostic insights that can guide supportive care and inform treatment planning in CAR-T therapy.展开更多
Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs tr...Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs trace fear memory by activating VIP neurons in the SCN,as demonstrated by increased c-Fos expression and Ca2+recording.This effect can be replicated and reversed through optogenetic and chemogenetic manipulations of SCN VIP neurons.Furthermore,we identify the SCN→PVT(paraventricular nucleus of the thalamus)VIP neuronal circuitry as essential in this process.These findings establish a novel role for SCN VIP neurons in modulating memory accessibility in response to environmental light cues,extending their known function beyond circadian regulation and revealing a mechanism for transient forgetting.展开更多
Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we ha...Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we have developed a novel charge-reversible nanogel to deliver paclitaxel(PTX)dimers(DPP)with enhanced stability and targeting precision.The nanogels exhibit a dynamic charge-reversal mechanism responsive to the acidic tumor microenvironment(TME),optimizing the cellular uptake of prodrugs.In the high glutathione(GSH)conditions within cancer cells,the disulfide bonds in the DPP are cleaved,resulting in the intracellular release of active PTX and reduced drug toxicity to normal cells.In vivo pharmacokinetic studies revealed an extended plasma elimination half-life for the charge-reversible nanocarriers,and antitumor efficacy studies demonstrated superior tumor suppression with minimal systemic toxicity.This research underscores the potential of integrating charge-reversal and responsive release mechanisms into one nanocarrier system,balancing the long circulation and high tumor cell internalization capacity of the nanocarrier,and providing a promising strategy for targeted delivery of nanomedicine.展开更多
Persistent and maladaptive drug-related memories represent a key component in drug addiction.Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconso...Persistent and maladaptive drug-related memories represent a key component in drug addiction.Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure(MRUP),a non-pharmacological strategy intertwining two distinct memory processes:reconsolidation and extinction—alternatively termed“the memory retrieval-extinction procedure”.This procedure presents a promising approach to attenuate,if not erase,entrenched drug memories and prevent relapse.The present review delineates the applications,molecular underpinnings,and operational boundaries of MRUP in the context of various forms of substance dependence.Furthermore,we critically examine the methodological limitations of MRUP,postulating potential refinement to optimize its therapeutic efficacy.In addition,we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction.Overall,existing studies underscore the significant potential of MRUP,suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.展开更多
Schizophrenia(SZ)stands as a severe psychiatric disorder.This study applied diffusion tensor imaging(DTI)data in conjunction with graph neural networks to distinguish SZ patients from normal controls(NCs)and showcases...Schizophrenia(SZ)stands as a severe psychiatric disorder.This study applied diffusion tensor imaging(DTI)data in conjunction with graph neural networks to distinguish SZ patients from normal controls(NCs)and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features,achieving an accuracy of 73.79%in distinguishing SZ patients from NCs.Beyond mere discrimination,our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis.These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers,providing novel insights into the neuropathological basis of SZ.In summary,our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.展开更多
Conventional PCR methods combined with linkage analysis based on short tandem repeats （STRs） or Karyomapping with single nucleotide polymorphism （SNP） arrays, have been applied to preimplantation genetic diagnosis...Conventional PCR methods combined with linkage analysis based on short tandem repeats （STRs） or Karyomapping with single nucleotide polymorphism （SNP） arrays, have been applied to preimplantation genetic diagnosis （PGD） for spinal muscular atrophy （SMA）, an autosome recessive disorder. However, it has limitations in SMA diagnosis by Karyomapping, and these methods are unable to distinguish wild- type embryos with carriers effectively. Mutated allele revealed by sequencing with aneuploidy and linkage analyses （MARSALA） is a new method allowing embryo selection by a one-step next-generation sequencing （NGS） procedure, which has been applied in PGD for both autosome dominant and X-linked diseases in our group previously. In this study, we carried out PGD based on MARSALA for two carrier families with SMA affected children. As a result, one of the couples has given birth to a healthy baby free of mutations in SMA-causing gene. It is the first time that MARSALA was applied to PGD for SMA, and we can distinguish the embryos with heterozygous deletion （carriers） from the wild-type （normal） ones accurately through this NGS-based method. In addition, direct mutation detection allows us to identify the affected embryos （homozygous deletion）, which can be regarded as probands for linkage analysis, in case that the affected family member is absent, In the future, the NGS-based MARSALA method is expected to be used in PGD for all monogenetic disorders with known pathogenic gene mutation.展开更多
Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate the...Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors(OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward,emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders,depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists(SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders,whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.展开更多
Major depressive disorder(MDD),also referred to as depression,is one of the most common psychiatric disorders with a high economic burden.The etiology of depression is still not clear,but it is generally believed that...Major depressive disorder(MDD),also referred to as depression,is one of the most common psychiatric disorders with a high economic burden.The etiology of depression is still not clear,but it is generally believed that MDD is a multifactorial disease caused by the interaction of social,psychological,and biological aspects.Therefore,there is no exact pathological theory that can independently explain its pathogenesis,involving genetics,neurobiology,and neuroimaging.At present,there are many treatment measures for patients with depression,including drug therapy,psychotherapy,and neuromodulation technology.In recent years,great progress has been made in the development of new antidepressants,some of which have been applied in the clinic.This article mainly reviews the research progress,pathogenesis,and treatment of MDD.展开更多
An ultimate goal of neuroscience is to decipher the principles underlying neuronal information processing at the molecular,cellular,circuit,and system levels.The advent of miniature fluorescence microscopy has further...An ultimate goal of neuroscience is to decipher the principles underlying neuronal information processing at the molecular,cellular,circuit,and system levels.The advent of miniature fluorescence microscopy has furthered the quest by visualizing brain activities and structural dynamics in animals engaged in self-determined behaviors.In this brief review,we summarize recent advances in miniature fluorescence microscopy for neuroscience,focusing mostly on two mainstream solutions-miniature single-photon microscopy,and miniature two-photon microscopy.We discuss their technical advantages and limitations as well as unmet challenges for future improvement.Examples of preliminary applications are also presented to reflect on a new trend of brain imaging in experimental paradigms involving body movements,long and complex protocols,and even disease progression and aging.展开更多
Single-cell RNA sequencing(scRNA-seq)has enabled high-resolution characterization of molecular signatures of tumor-infiltrating lymphocytes.However,analyses at the transcript isoform level are rarely reported.As alter...Single-cell RNA sequencing(scRNA-seq)has enabled high-resolution characterization of molecular signatures of tumor-infiltrating lymphocytes.However,analyses at the transcript isoform level are rarely reported.As alternative splicing is critical to T-cell differentiation and activation,here,we proposed a computational method named IDEA(Issoform Detection.Enrichment,and functional Annotation)to comprehensively detect and annotate differentially used isoforms across cell subtypes.We applied IDEA on a scRNA-seq data set of 12,346 T cells from non-small-cell lung cancer(NSCLC).we found that most genes tend to dominantly express one isoform in single T cells,enabling typing T cells based on the isotypes.given a gene.lsotype analysis suggested that tumor-infiltrating Tcells significantly preferred specific isotypes for 245 genes in CD8t Tcells and 456 genes in CD4^+T cells.Functional annotation suggests that the preferred isoforms involved in coding/noncoding switches,transcription start site changes,gains/losses of domains,and subcellular translocation.Clonal analysis revealed that isoform switching occurred during T-cell activation/differentiation.Our analysis provides precise characterization of the molecular events in tumor-infiltrating T cells and sheds new light on the regulatory mechanisms oftumor-infiltrating T cells.展开更多
Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties.It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere,consequently imposing devastating social,e...Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties.It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere,consequently imposing devastating social,economic,and health burdens worldwide.However,the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown,and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce.This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action,including neural circuit dysfunction and neuroinflammation.We discuss recent progress in the development of pharmacological interventions,anti-fentanyl vaccines,anti-fentanyl/heroin conjugate vaccines,and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression.However,translational studies and clinical trials are still lacking.Considering the present opioid crisis,the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.展开更多
In plants, RNA editing is a post-transcriptional process that changes specific cytidine to uridine in both mitochondria and plastids. Most pentatricopeptide repeat（PPR） proteins are involved in organelle RNA editing...In plants, RNA editing is a post-transcriptional process that changes specific cytidine to uridine in both mitochondria and plastids. Most pentatricopeptide repeat（PPR） proteins are involved in organelle RNA editing by recognizing specific RNA sequences. We here report the functional characterization of a PPR protein from the DYW subclass, Baili Xi（BLX）, which contains five PPR motifs and a DYW domain. BLX is essential for early seed development, as plants lacking the BLX gene was embryo lethal and the endosperm failed to initiate cellularization. BLX was highly expressed in the embryo and endosperm, and the BLX protein was specifically localized in mitochondria, which is essential for BLX function. We found that BLX was required for the efficient editing of 36 editing sites in mitochondria. Moreover, BLX was involved in the splicing regulation of the fourth intron of nad1 and the first intron of nad2. The loss of BLX function impaired the mitochondrial function and increased the reactive oxygen species（ROS） level. Genetic complementation with truncated variants of BLX revealed that, in addition to the DYW domain, only the fifth PPR motif was essential for BLX function. The upstream sequences of the BLX-targeted editing sites are not conserved, suggesting that BLX serves as a novel and major mitochondrial editing factor（MEF） via a new non-RNA-interacting manner. This finding provides new insights into how a DYW-type PPR protein with fewer PPR motifs regulates RNA editing in plants.展开更多
Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation,and circadian disturbances are often found in patients with major depressive disorder(MDD).The mitogen-activated protei...Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation,and circadian disturbances are often found in patients with major depressive disorder(MDD).The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)pathway is involved in mediating entrainment of the circadian system.Furthermore,the MAPK/ERK signaling pathway has been shown to be involved in the pathogenesis of MDD and the rapid onset of action of antidepressant therapies,both pharmaceutical and non-pharmaceutical.This review provides an overview of the involvement of the MAPK/ERK pathway in modulating the circadian system in the rapid action of antidepressant therapies.This pathway holds much promise for the development of novel,rapid-onset-of-action therapeutics for MDD.展开更多
We aimed to develop a disease risk comorbidity index(DRCI)based on disease risk index(DRI)and Hematopoietic Cell Transplantation-Specific Comorbidity Index(HCT-CI)in patients receiving haploidentical hematopoietic ste...We aimed to develop a disease risk comorbidity index(DRCI)based on disease risk index(DRI)and Hematopoietic Cell Transplantation-Specific Comorbidity Index(HCT-CI)in patients receiving haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We identified the prognostic factors of disease-free survival(DFS)in a training subset(n=593),then assigned a weighted score using these factors to the remaining patients(validation subset;n=296).The multivariable model identified two independent predictors of DFS:DRI and HCT-CI before transplantation.In this scoring system,we assigned a weighted score of 2 to very high-risk DRI,and assigned a weighted score of 1 to high-risk DRI and intermediate-and high-risk HCT-CI(i.e.,haplo-DRCI).In the validation cohort,the three-year DFS rate was 65.2%(95%confidence interval(CI),58.2%–72.2%),55.8%(95%CI,44.9%–66.7%),and 32.0%(95%CI,5.8%–58.2%)for the low-,intermediate-,and high-risk group,respectively(P=0.005).Haplo-DRCI can also predict DFS in disease-specific subgroups,particularly in acute leukemia patients.Increasing score was also significantly predictive of increased relapse,increased non-relapse mortality(NRM),decreased DFS,and decreased overall survival(OS)in an independent historical cohort(n=526).These data confirmed that haplo-DRCI could effectively risk stratify haplo-HSCT recipients and provide a tool to better predict who will best benefit from haplo-HSCT.展开更多
Objective: Challenges remain in current practices of colorectal cancer(CRC) screening, such as low compliance,low specificities and expensive cost. This study aimed to identify high-risk groups for CRC from the genera...Objective: Challenges remain in current practices of colorectal cancer(CRC) screening, such as low compliance,low specificities and expensive cost. This study aimed to identify high-risk groups for CRC from the general population using regular health examination data.Methods: The study population consist of more than 7,000 CRC cases and more than 140,000 controls. Using regular health examination data, a model detecting CRC cases was derived by the classification and regression trees(CART) algorithm. Receiver operating characteristic(ROC) curve was applied to evaluate the performance of models. The robustness and generalization of the CART model were validated by independent datasets. In addition, the effectiveness of CART-based screening was compared with stool-based screening.Results: After data quality control, 4,647 CRC cases and 133,898 controls free of colorectal neoplasms were used for downstream analysis. The final CART model based on four biomarkers(age, albumin, hematocrit and percent lymphocytes) was constructed. In the test set, the area under ROC curve(AUC) of the CART model was 0.88 [95%confidence interval(95% CI), 0.87-0.90] for detecting CRC. At the cutoff yielding 99.0% specificity, this model’s sensitivity was 62.2%(95% CI, 58.1%-66.2%), thereby achieving a 63-fold enrichment of CRC cases. We validated the robustness of the method across subsets of test set with diverse CRC incidences, aging rates, genders ratio, distributions of tumor stages and locations, and data sources. Importantly, CART-based screening had the higher positive predictive value(1.6%) than fecal immunochemical test(0.3%).Conclusions: As an alternative approach for the early detection of CRC, this study provides a low-cost method using regular health examination data to identify high-risk individuals for CRC for further examinations. The approach can promote early detection of CRC especially in developing countries such as China, where annual health examination is popular but regular CRC-specific screening is rare.展开更多
基金supported by the Beijing Natural Science Foundation(No.Z230016)the National Key Research and Development Program of China(No.2022YFC 2502606)+4 种基金the Major Program of the National Natural Science Foundation of China(No.82293630)the Peking University Medicine Fund for the World’s Leading Discipline or Discipline Cluster Development(No.71003Y3035)the Plan Project of Tongzhou Municipal Science and Technology(No.KJ2024CX045)the National Natural Science Foundation of China(No.82170208)the Fundamental Research Funds for the Central Universities。
文摘Objective:Adverse-risk acute myeloid leukemia(AML)patients should receive allogeneic hematopoietic stem cell transplantation(allo-HSCT)at first complete remission(CR1).However,the influence of prior therapies[i.e.,venetoclax plus azacitidine(VEN-AZA)or intensive chemotherapy(IC)]on post-transplant outcomes remains inconclusive.This multicenter,retrospective study compared the post-transplant outcomes between patients receiving VEN-AZA and those receiving IC before allo-HSCT.Methods:This study was based on the transplant database of TROPHY group.Consecutive adverse-risk AML patients receiving allo-HSCT from January 2021 to June 2023 were screened in five Chinese transplant centers.Patients were categorized into VEN-AZA group if they received venetoclax combined with azacitidine as first-line therapy followed by allo-HSCT.Patients who received first-line therapy consisting of a mainstay treatment of cytarabine and anthracycline followed by allo-HSCT were categorized into IC group.Results:In the total cohort,the 3-year probabilities of overall survival,leukemia-free survival,and event-free survival were better in the IC group than VEN-AZA group,particularly for patients with ASXL1 mutations or SF3B1 mutations.However,the survival of the VEN-AZA group was not superior to that of IC group in patients aged≥55 years or those with the hematopoietic cell transplantation-comorbidity index scores≥1 before allo-HSCT.After propensity score matching(median age:VEN-AZA group:57 years;IC group:55 years),only the probability of overall survival for the IC group was better than that of VEN-AZA group(93.6%vs.78.0%,P=0.034)at the 1-year follow-up;however,all of the other clinical outcomes were comparable between the VEN-AZA and IC groups.The TP53 mutation was independently associated with post-transplant relapse and survival.Conclusions:Our results suggest that IC remains the cornerstone of therapy,whereas VEN-AZA may also be used in younger patients and medically fit patients with adverse-risk AML who are receiving allo-HSCT in CR1.
基金supported by the Biological Breeding-National Science and Technology Major Project(2024ZD04077).
文摘Remodeling plant intracellular nucleotide-binding leucine-rich repeat immune receptors(NLRs)to engineer synthetic disease-resistance genes has emerged as a promising approach to achieving broad-spectrum disease resistance.But strategies for expanding NLR recognition spectra[[1],[2],[3],[4],[5]]are often limited by the rapid evolution of pathogens and pests.In our recent study,we developed an innovative strategy to engineer broad-spectrum,durable and complete disease resistance in plants by remodeling autoactive NLRs into protease-activated switches[6].
文摘Since 1968 when the first successful hematopoietic stem cell transplantation(HSCT) was performed, transplant technique has developed rapidly for more than 50 years. In the past 20 years, the significant breakthroughs and widely use of haploidentical-related donor HSCT(e.g. Beijing Protocol) make everyone can have a donor(1), and the novel, reduced-toxicity transplant regimens help elderly patients receive HSCT safely(2).
基金financial support from National Natural Science Foundation of China(No.12375336,11875078)。
文摘Stretchability is a crucial property of flexible all-in-one supercapacitors.This work reports a novel hydrogel electrolyte,polyacrylamidedivinylbenzene-Li2SO4(PAM-DVB-Li)synthesized by using a strategy of combining hydrophobic nodes and hydrophilic networks as well as a method of dispersing hydrophobic DVB crosslinker to acrylamide monomer/Li2SO4 aqueous solution by micelles and followedγ-radiation induced polymerization and crosslinking.The resultant PAM-DVB-Li hydrogel electrolyte possesses excellent mechanical properties with 5627±241%stretchability and high ionic conductivity of 53±3 mS cm^(-1).By in situ polymerization of conducting polyaniline(PANI)on the PAM-DVB-Li hydrogel electrolyte,a novel all-in-one supercapacitor,PAM-DVB-Li/PANI,with highly integrated structure is prepared further.Benefiting from the excellent properties of hydrogel electrolyte and the all-in-one structure,the device exhibits a high specific capacitance of 469 mF cm^(-2) at 0.5 mA cm^(-2),good cyclic stability,safety,and deformation damage resistance.More importantly,the device demonstrates a superior tensile resistance(working normally under no more than 300%strain,capacitance stability in 1000 cycles of 1000%stretching and 10 cycles of 3000%stretching)far beyond that of other all-in-one supercapacitors.This work proposes a novel strategy to construct tensile-resistant all-in-one flexible supercapacitors that can be used as an energy storage device for stretchable electronic devices.
基金supported by the National Nature Science Foundation of China(82174085)Natural Science Foundation of Inner Mongolia Autonomous Region(2019MS08032).
文摘Alzheimer’s disease(AD)is a degenerative disease of the central nervous system.It results in cognitive dysfunction due to the loss of functional neurons and a deficit of new neurons,which can lead to death in severe cases.Repairing damaged neurons by promoting hippocampal neurogenesis has become therapeutic modality to combat neurodegenerative diseases.The novel isoflavone alkaloid LY01,found in the edible fruits of Sophora alopecuroides L.,has various neuroprotective effects.However,the molecular mechanism by which it promotes the proliferation of endogenous neural stem cells(NSCs)is not yet precisely known.The effects of LY01 were investigated in vivo and in vitro.In vivo experiments showed that LY01 could counteract the toxic damage of amyloid β-protein(Aβ),enhance the learning ability and memory capacity of 5×FAD mice,and improve the morphology of neurons in the hippocampal region.In vitro experiments showed that LY01 was effective against antioxidant damage,improved the cell morphology of C17.2 mouse NSCs after hydrogen peroxide injury,and increased cell viability.Both in vitro and in vivo experiments promoted NSC proliferation by upregulating the mRNA and protein levels of the critical genes of the Wnt/β-catenin pathway,which increased levels of doublecortin to facilitate new neuronal generation.This indicates that the ability of LY01 to counteract Aβ toxicity and alleviate oxidative damage in early AD is associated with activation of the Wnt/β-catenin signaling pathway to promote NSC proliferation and thus repair damaged neurons.
基金supported by National Key Research and Development Plan of China(No.2022YFC2502606,2021YFA1100902)Beijing Nova Program of Science and Technology(No.20230484446)+2 种基金Peking University People’s Hospital(No.RZ2024-01)Joint Research Project of the Shijiazhuang-Peking University Cooperation Program,Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0501200)National Natural Science Foundation of China(No.82350105,82270228)。
文摘Objective:Immune effector cell-associated hematotoxicity(ICAHT),characterized by prolonged cytopenia and delayed hematopoietic recovery,is a common complication following chimeric antigen receptor T(CAR-T)cell therapy.However,the applicability of existing predictive models,CAR-HEMATOTOX(CAR-HT)for lymphoma,acute lymphoblastic leukemia-HEMATOTOX(ALL-HT)for B-ALL,and the early ICAHT prediction model(e IPM),remains uncertain across different hematologic malignancies.Methods:We prospectively analyzed 119 patients who received CAR-T therapy between January 2022 and June2025,including B-ALL(n=62),T-ALL/non-Hodgkin's lymphoma(NHL)(n=25),and multiple myeloma(MM,n=32).The CAR-HT,ALL-HT,and e IPM models were evaluated for their ability to predict ICAHT severity and survival outcomes.Results:Grade 3 ICAHT occurred in 32.3%of B-ALL,40.0%of T-ALL/NHL,and 25.0%of MM patients,while grade 4 rates were 33.9%,20.0%,and 6.3%,respectively.CAR-HT classified 67.2%of patients as high-risk,and ALL-HT identified 56.3%of ALL/NHL patients as high-risk.In both models,high-risk groups experienced significantly more prolonged neutropenia than low-risk groups(CAR-HT:17.7 vs.5.3 d,P<0.001;ALL-HT:21.3 vs.7.7 d,P<0.001).Both e IPMpre and e IPMpost strongly correlated with grade 3-4 ICAHT(P<0.001).Importantly,survival analysis showed that e IPMpre stratification distinguished outcomes:1-year overall survival(OS)was 65%in medium+high-risk vs.84%in low-risk patients(P=0.006),and 1-year disease-free survival(DFS)was 44%vs.73%(P<0.001).Similar predictive accuracy was observed with e IPMpost.Conclusions:The CAR-HT,ALL-HT,and e IPM models consistently identify patients at high risk for severe ICAHT across B-ALL,T-ALL/NHL,and MM.Among these,the e IPM stands out as a promising universal tool for survival prediction.These models provide valuable prognostic insights that can guide supportive care and inform treatment planning in CAR-T therapy.
基金supported by grants from the National Natural Science Foundation of China(32021002 and 31900724)the STI2030-Major Projects(2022ZD0204900)the Tsinghua-Peking Joint Center for Life Sciences.
文摘Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs trace fear memory by activating VIP neurons in the SCN,as demonstrated by increased c-Fos expression and Ca2+recording.This effect can be replicated and reversed through optogenetic and chemogenetic manipulations of SCN VIP neurons.Furthermore,we identify the SCN→PVT(paraventricular nucleus of the thalamus)VIP neuronal circuitry as essential in this process.These findings establish a novel role for SCN VIP neurons in modulating memory accessibility in response to environmental light cues,extending their known function beyond circadian regulation and revealing a mechanism for transient forgetting.
基金supported by the Natural Science Foundation of Jilin Province(No.20240101003JJ)the National Natural Science Foundation of China(Nos.22275065,52073116)。
文摘Nanomedicine holds considerable promise for advancing cancer therapy,however,effective delivery of drugs to solid tumors remains a challenge due to rapid systemic clearance and inefficient cellular uptake.Herein,we have developed a novel charge-reversible nanogel to deliver paclitaxel(PTX)dimers(DPP)with enhanced stability and targeting precision.The nanogels exhibit a dynamic charge-reversal mechanism responsive to the acidic tumor microenvironment(TME),optimizing the cellular uptake of prodrugs.In the high glutathione(GSH)conditions within cancer cells,the disulfide bonds in the DPP are cleaved,resulting in the intracellular release of active PTX and reduced drug toxicity to normal cells.In vivo pharmacokinetic studies revealed an extended plasma elimination half-life for the charge-reversible nanocarriers,and antitumor efficacy studies demonstrated superior tumor suppression with minimal systemic toxicity.This research underscores the potential of integrating charge-reversal and responsive release mechanisms into one nanocarrier system,balancing the long circulation and high tumor cell internalization capacity of the nanocarrier,and providing a promising strategy for targeted delivery of nanomedicine.
基金supported by the National Natural Science Foundation of China(82071498,81871046,and 32161143022)STI2030-Major Projects(2022ZD0214500).
文摘Persistent and maladaptive drug-related memories represent a key component in drug addiction.Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure(MRUP),a non-pharmacological strategy intertwining two distinct memory processes:reconsolidation and extinction—alternatively termed“the memory retrieval-extinction procedure”.This procedure presents a promising approach to attenuate,if not erase,entrenched drug memories and prevent relapse.The present review delineates the applications,molecular underpinnings,and operational boundaries of MRUP in the context of various forms of substance dependence.Furthermore,we critically examine the methodological limitations of MRUP,postulating potential refinement to optimize its therapeutic efficacy.In addition,we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction.Overall,existing studies underscore the significant potential of MRUP,suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.
基金supported by the National Natural Science Foundation of China(62276049,61701078,61872068,and 62006038)the Natural Science Foundation of Sichuan Province(2025ZNSFSC0487)+3 种基金the Science and Technology Innovation 2030-Brain Science and Brain-Inspired Intelligence Project(2021ZD0200200)the National Key R&D Program of China(2023YFE0118600)Sichuan Province Science and Technology Support Program(2019YJ0193,2021YFG0126,2021YFG0366,and 2022YFS0180)Medico-Engineering Cooperation Funds from the University of Electronic Science and Technology of China(ZYGX2021YGLH014).
文摘Schizophrenia(SZ)stands as a severe psychiatric disorder.This study applied diffusion tensor imaging(DTI)data in conjunction with graph neural networks to distinguish SZ patients from normal controls(NCs)and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features,achieving an accuracy of 73.79%in distinguishing SZ patients from NCs.Beyond mere discrimination,our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis.These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers,providing novel insights into the neuropathological basis of SZ.In summary,our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
基金supported by the National Natural Science Foundation of China (Nos. 31522034, 31571544 and 31230047)the National High Technology Research and Development Program (No. 2015AA020407)+1 种基金Beijing Municipal Science and Technology Commission (No. D151100002415004)Research Fund of National Health and Family Planning Commission of China (No. 201402004)
文摘Conventional PCR methods combined with linkage analysis based on short tandem repeats （STRs） or Karyomapping with single nucleotide polymorphism （SNP） arrays, have been applied to preimplantation genetic diagnosis （PGD） for spinal muscular atrophy （SMA）, an autosome recessive disorder. However, it has limitations in SMA diagnosis by Karyomapping, and these methods are unable to distinguish wild- type embryos with carriers effectively. Mutated allele revealed by sequencing with aneuploidy and linkage analyses （MARSALA） is a new method allowing embryo selection by a one-step next-generation sequencing （NGS） procedure, which has been applied in PGD for both autosome dominant and X-linked diseases in our group previously. In this study, we carried out PGD based on MARSALA for two carrier families with SMA affected children. As a result, one of the couples has given birth to a healthy baby free of mutations in SMA-causing gene. It is the first time that MARSALA was applied to PGD for SMA, and we can distinguish the embryos with heterozygous deletion （carriers） from the wild-type （normal） ones accurately through this NGS-based method. In addition, direct mutation detection allows us to identify the affected embryos （homozygous deletion）, which can be regarded as probands for linkage analysis, in case that the affected family member is absent, In the future, the NGS-based MARSALA method is expected to be used in PGD for all monogenetic disorders with known pathogenic gene mutation.
基金the National Natural Science Foundation of China(81701312 and 81521063)the Interdisciplinary Medicine Seed Fund of Peking University(BMU2018MX024).
文摘Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors(OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward,emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders,depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists(SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders,whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.
基金This review was supported by the National Basic Research Development Program of China(2016YFC1307100)the National Natural Science Foundation of China(81930033 and 81771465+6 种基金81401127)Shanghai Key Project of Science&Technology(2018SHZDZX05)Shanghai Jiao Tong University Medical Engineering Foundation(YG2016MS48)Shanghai Jiao Tong University School of Medicine(19XJ11006)the Sanming Project of Medicine in Shenzhen Municipality(SZSM201612006)the National Key Technologies R&D Program of China(2012BAI01B04)the Innovative Research Team of High-level Local Universities in Shanghai.
文摘Major depressive disorder(MDD),also referred to as depression,is one of the most common psychiatric disorders with a high economic burden.The etiology of depression is still not clear,but it is generally believed that MDD is a multifactorial disease caused by the interaction of social,psychological,and biological aspects.Therefore,there is no exact pathological theory that can independently explain its pathogenesis,involving genetics,neurobiology,and neuroimaging.At present,there are many treatment measures for patients with depression,including drug therapy,psychotherapy,and neuromodulation technology.In recent years,great progress has been made in the development of new antidepressants,some of which have been applied in the clinic.This article mainly reviews the research progress,pathogenesis,and treatment of MDD.
基金We thank Dr.Zhe Zhao and Dr.Haitao Wu for helping with the experiments for Fig.2D,and Dr.Weijian Zong for discussion.This work was supported by grants from the National Natural Science Foundation of China(31327901,31570839,61975002,31830036,31821091,and 8182780030)the Major State Basic Research Program of China(2016 YFA0500400 and 2016YFA0500403)and the National Postdoctoral Program for Innovative Talents of China(BX20190011).
文摘An ultimate goal of neuroscience is to decipher the principles underlying neuronal information processing at the molecular,cellular,circuit,and system levels.The advent of miniature fluorescence microscopy has furthered the quest by visualizing brain activities and structural dynamics in animals engaged in self-determined behaviors.In this brief review,we summarize recent advances in miniature fluorescence microscopy for neuroscience,focusing mostly on two mainstream solutions-miniature single-photon microscopy,and miniature two-photon microscopy.We discuss their technical advantages and limitations as well as unmet challenges for future improvement.Examples of preliminary applications are also presented to reflect on a new trend of brain imaging in experimental paradigms involving body movements,long and complex protocols,and even disease progression and aging.
基金Beijing Advanced lnnovation Centre for Genomics at Peking University,Key Technologies R&D Program(2016YFCO900100)the National Natural Science Foundation of China(31991171,31530036,91742203,and 9194230046).
文摘Single-cell RNA sequencing(scRNA-seq)has enabled high-resolution characterization of molecular signatures of tumor-infiltrating lymphocytes.However,analyses at the transcript isoform level are rarely reported.As alternative splicing is critical to T-cell differentiation and activation,here,we proposed a computational method named IDEA(Issoform Detection.Enrichment,and functional Annotation)to comprehensively detect and annotate differentially used isoforms across cell subtypes.We applied IDEA on a scRNA-seq data set of 12,346 T cells from non-small-cell lung cancer(NSCLC).we found that most genes tend to dominantly express one isoform in single T cells,enabling typing T cells based on the isotypes.given a gene.lsotype analysis suggested that tumor-infiltrating Tcells significantly preferred specific isotypes for 245 genes in CD8t Tcells and 456 genes in CD4^+T cells.Functional annotation suggests that the preferred isoforms involved in coding/noncoding switches,transcription start site changes,gains/losses of domains,and subcellular translocation.Clonal analysis revealed that isoform switching occurred during T-cell activation/differentiation.Our analysis provides precise characterization of the molecular events in tumor-infiltrating T cells and sheds new light on the regulatory mechanisms oftumor-infiltrating T cells.
基金the National Key Research and Development Program of China(2019YFC0118604)the National Natural Science Foundation of China(32071058).
文摘Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties.It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere,consequently imposing devastating social,economic,and health burdens worldwide.However,the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown,and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce.This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action,including neural circuit dysfunction and neuroinflammation.We discuss recent progress in the development of pharmacological interventions,anti-fentanyl vaccines,anti-fentanyl/heroin conjugate vaccines,and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression.However,translational studies and clinical trials are still lacking.Considering the present opioid crisis,the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.
基金supported by the National Natural Science Foundation of China(Nos.31620103903 and 31621001)partially by the 111 projectsupported by the Peking-Tsinghua Joint Center for Life Sciences
文摘In plants, RNA editing is a post-transcriptional process that changes specific cytidine to uridine in both mitochondria and plastids. Most pentatricopeptide repeat（PPR） proteins are involved in organelle RNA editing by recognizing specific RNA sequences. We here report the functional characterization of a PPR protein from the DYW subclass, Baili Xi（BLX）, which contains five PPR motifs and a DYW domain. BLX is essential for early seed development, as plants lacking the BLX gene was embryo lethal and the endosperm failed to initiate cellularization. BLX was highly expressed in the embryo and endosperm, and the BLX protein was specifically localized in mitochondria, which is essential for BLX function. We found that BLX was required for the efficient editing of 36 editing sites in mitochondria. Moreover, BLX was involved in the splicing regulation of the fourth intron of nad1 and the first intron of nad2. The loss of BLX function impaired the mitochondrial function and increased the reactive oxygen species（ROS） level. Genetic complementation with truncated variants of BLX revealed that, in addition to the DYW domain, only the fifth PPR motif was essential for BLX function. The upstream sequences of the BLX-targeted editing sites are not conserved, suggesting that BLX serves as a novel and major mitochondrial editing factor（MEF） via a new non-RNA-interacting manner. This finding provides new insights into how a DYW-type PPR protein with fewer PPR motifs regulates RNA editing in plants.
基金This review was supported by the National Basic Research Development Program of China(2015CB856400,2015CB553503)the National Natural Science Foundation of China(81521063)the Natural Science Foundation of Beijing Municipality,China(7162101).
文摘Accumulating evidence suggests that the circadian rhythm plays a critical role in mood regulation,and circadian disturbances are often found in patients with major depressive disorder(MDD).The mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)pathway is involved in mediating entrainment of the circadian system.Furthermore,the MAPK/ERK signaling pathway has been shown to be involved in the pathogenesis of MDD and the rapid onset of action of antidepressant therapies,both pharmaceutical and non-pharmaceutical.This review provides an overview of the involvement of the MAPK/ERK pathway in modulating the circadian system in the rapid action of antidepressant therapies.This pathway holds much promise for the development of novel,rapid-onset-of-action therapeutics for MDD.
基金This work was supported by the National Key Research and Development Program of China(2017YFA0104500)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81621001)+6 种基金the Key Program of the National Natural Science Foundation of China(81930004)Capital’s Funds for Health Improvement and Research(2018-4-4089)CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-034)the Science and Technology Project of Guangdong Province of China(2016B030230003)the Project of Health Collaborative Innovation of Guangzhou City(201704020214)Peking University Clinical Scientist Program(BMU2019LCKXJ003)supported by the Fundamental Research Funds for the Central Universities.
文摘We aimed to develop a disease risk comorbidity index(DRCI)based on disease risk index(DRI)and Hematopoietic Cell Transplantation-Specific Comorbidity Index(HCT-CI)in patients receiving haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We identified the prognostic factors of disease-free survival(DFS)in a training subset(n=593),then assigned a weighted score using these factors to the remaining patients(validation subset;n=296).The multivariable model identified two independent predictors of DFS:DRI and HCT-CI before transplantation.In this scoring system,we assigned a weighted score of 2 to very high-risk DRI,and assigned a weighted score of 1 to high-risk DRI and intermediate-and high-risk HCT-CI(i.e.,haplo-DRCI).In the validation cohort,the three-year DFS rate was 65.2%(95%confidence interval(CI),58.2%–72.2%),55.8%(95%CI,44.9%–66.7%),and 32.0%(95%CI,5.8%–58.2%)for the low-,intermediate-,and high-risk group,respectively(P=0.005).Haplo-DRCI can also predict DFS in disease-specific subgroups,particularly in acute leukemia patients.Increasing score was also significantly predictive of increased relapse,increased non-relapse mortality(NRM),decreased DFS,and decreased overall survival(OS)in an independent historical cohort(n=526).These data confirmed that haplo-DRCI could effectively risk stratify haplo-HSCT recipients and provide a tool to better predict who will best benefit from haplo-HSCT.
基金supported by funding from Beijing Municipal Science & Technology Commission, Clinical Application and Development of Capital Characteristic (No. Z161100000516003)National Natural Science Foundation of China (No. 31871266)
文摘Objective: Challenges remain in current practices of colorectal cancer(CRC) screening, such as low compliance,low specificities and expensive cost. This study aimed to identify high-risk groups for CRC from the general population using regular health examination data.Methods: The study population consist of more than 7,000 CRC cases and more than 140,000 controls. Using regular health examination data, a model detecting CRC cases was derived by the classification and regression trees(CART) algorithm. Receiver operating characteristic(ROC) curve was applied to evaluate the performance of models. The robustness and generalization of the CART model were validated by independent datasets. In addition, the effectiveness of CART-based screening was compared with stool-based screening.Results: After data quality control, 4,647 CRC cases and 133,898 controls free of colorectal neoplasms were used for downstream analysis. The final CART model based on four biomarkers(age, albumin, hematocrit and percent lymphocytes) was constructed. In the test set, the area under ROC curve(AUC) of the CART model was 0.88 [95%confidence interval(95% CI), 0.87-0.90] for detecting CRC. At the cutoff yielding 99.0% specificity, this model’s sensitivity was 62.2%(95% CI, 58.1%-66.2%), thereby achieving a 63-fold enrichment of CRC cases. We validated the robustness of the method across subsets of test set with diverse CRC incidences, aging rates, genders ratio, distributions of tumor stages and locations, and data sources. Importantly, CART-based screening had the higher positive predictive value(1.6%) than fecal immunochemical test(0.3%).Conclusions: As an alternative approach for the early detection of CRC, this study provides a low-cost method using regular health examination data to identify high-risk individuals for CRC for further examinations. The approach can promote early detection of CRC especially in developing countries such as China, where annual health examination is popular but regular CRC-specific screening is rare.
