Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable...Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential.These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature.Inspired by their unique properties,thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine.In this review,the state-of-theart developments in thermosensitive hydrogels for precision therapy are investigated,which covers from the thermo-gelling mechanisms and main components to biomedical applications,including wound healing,anti-tumor activity,osteogenesis,and periodontal,sinonasal and ophthalmic diseases.The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.展开更多
Organoids are three-dimensional stem cell-derived models that offer a more physiologically relevant representation of tumor biology compared to traditional two-dimensional cell cultures or animal models.Organoids pres...Organoids are three-dimensional stem cell-derived models that offer a more physiologically relevant representation of tumor biology compared to traditional two-dimensional cell cultures or animal models.Organoids preserve the complex tissue architecture and cellular diversity of human cancers,enabling more accurate predictions of tumor growth,metastasis,and drug responses.Integration with microfluidic platforms,such as organ-on-a-chip systems,further enhances the ability to model tumor-environment interactions in real-time.Organoids facilitate in-depth exploration of tumor heterogeneity,molecular mechanisms,and the development of personalized treatment strategies when coupled with multi-omics technologies.Organoids provide a platform for investigating tumor-immune cell interactions,which aid in the design and testing of immune-based therapies and vaccines.Taken together,these features position organoids as a transformative tool in advancing cancer research and precision medicine.展开更多
Background:Oral squamous cell carcinoma(OSCC)is a prevalent type of cancer with a high mortality rate in its late stages.One of the major challenges in OSCC treatment is the resistance to epidermal growth factor recep...Background:Oral squamous cell carcinoma(OSCC)is a prevalent type of cancer with a high mortality rate in its late stages.One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor(EGFR)inhibitors.Therefore,it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy.Methods:To evaluate the efficacy of the combination of the Ca^(2+)/calmodulin-dependent protein kinase II(CAMK2)inhibitor KN93 and EGFR inhibitors,we performed in vitro and in vivo experiments using two FAT atypical cadherin 1(FAT1)-deficient(SCC9 and SCC25)and two FAT1 wild-type(SCC47 and HN12)OSCC cell lines.We assessed the effects of EGFR inhibitors(afatinib or cetuximab),KN93,or their combination on the malignant phenotype of OSCC in vivo and in vitro.The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2(SOX2)were analyzed.Changes in the yes-associated protein 1(YAP1)protein were characterized.Moreover,we analyzed mitochondrial dysfunction.Besides,the effects of combination therapy on mitochondrial dynamics were also evaluated.Results:OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment.The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation,survival,and migration of FAT1-mutated OSCC cells and suppressed tumor growth in vivo.Mechanistically,combination therapy enhanced the therapeutic sensitivity of FAT1-mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins.Furthermore,combination therapy induced reactive oxygen species(ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics,ultimately resulting in tumor suppression.Conclusion:Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.展开更多
Multicellular three-dimensional(3D)bioprinting technology,a pivotal in vitro approach in tissue engineering and disease modeling,enables the co-culture of multiple cell populations within 3D architectures while preser...Multicellular three-dimensional(3D)bioprinting technology,a pivotal in vitro approach in tissue engineering and disease modeling,enables the co-culture of multiple cell populations within 3D architectures while preserving physiological interactions(1).This strategy facilitates the precise simulation of human histogenesis and pathogenesis through four principal modalities:organoid-based systems that recapitulate tissue self-organization,air-liquid interface(ALI)platforms facilitating epithelial-mesenchymal crosstalk analysis,3D microfluidic devices for spatiotemporal control of biomolecular gradients,and bioprinting techniques achieving micron-level spatial patterning of heterogeneous cells(2).Each modality addresses distinct experimental demands in reconstructing multicellular microenvironments,collectively enhancing the fidelity of drug screening and advancing mechanobiological research.展开更多
Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through ...Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through the harsh gastrointestinal environment and intestinal mucus barrier.To overcome the gastrointestinal barriers for oral drug delivery mentioned above,a“spore-like”oral nanodrug delivery platform(Cur/COS/SC NPs)has been developed.Firstly,chitooligosaccharides(COS)are encapsulated on the surface of Curcumin nanoparticles(Cur NPs)to form carrier-free nanoparticles(Cur/COS NPs).Subsequently,inspired by the natural high resistance of spore coat(SC),SC is chosen as the“protective umbrella”to encapsulate Cur/COS NPs for precision targeted therapy of IBD.After oral administration,SC can effectively protect NPs through the rugged gastrointestinal environment and exhibit excellent intestinal mucus penetration characteristics.Moreover,the negatively-charged Cur/COS/SC NPs specifically target positivelycharged inflamed colon via electrostatic interactions.It is demonstrated that Cur/COS/SC NPs can promote the expression of tight junction proteins,inhibit aberrant activation of the Toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB(TLR4/MyD88/NF-κB)signaling pathway,and downregulate the levels of pro-inflammatory factors,exhibiting excellent anti-inflammatory effects.Notably,it is found that Cur/COS/SC NPs can significantly increase the richness and diversity of gut microbiota,and restore the homeostasis of gut microbiota by inhibiting pathogenic bacteria and promoting probiotics.Hence,Cur/COS/SC NPs provide a safe,efficient,and feasible new strategy for IBD treatment.展开更多
The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough establ...The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough established a novel framework for site-specific gene delivery through repurposing ancient viral tools.展开更多
BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast ...BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.展开更多
Precision medicine aims to identify the right drug, for the right patient, at the right dose, at the right time, which is particularly important in cancer therapy. Problems such as the variability of treatment respons...Precision medicine aims to identify the right drug, for the right patient, at the right dose, at the right time, which is particularly important in cancer therapy. Problems such as the variability of treatment response and resistance to medication have been longstanding challenges in oncology, especially for development of new medications. Solid tumors, unlike hematologic malignancies or brain tumors, are remarkably diverse in their cellular origins and developmental timing. The ability of next-generation sequencing(NGS) to analyze the comprehensive landscape of genetic alterations brings promises to diseases that have a highly complex and heterogeneous genetic composition such as cancer. Here we provide an overview of how NGS is able to facilitate precision medicine and change the paradigm of cancer therapy, especially for solid tumors, through technical advancements, molecular diagnosis, response monitoring and clinical trials.展开更多
Ovarian cancer is one of the most common malignant tumors in female reproductive organs.Due to the lack of effective screening and early diagnosis methods,the vast majority of patients with ovarian cancer are in advan...Ovarian cancer is one of the most common malignant tumors in female reproductive organs.Due to the lack of effective screening and early diagnosis methods,the vast majority of patients with ovarian cancer are in advanced stages once diagnosed.Precision therapy mainly includes immunotherapy,targeted therapy,biological therapy,and gene therapy.At present,precision therapy is increasingly used in the clinical treatment of ovarian cancer due to its advantages,such as fewer side effects and a high degree of killing.This article summarizes the recent advances in the precise treatment of ovarian cancer.展开更多
Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to...Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood circulation.To address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors.These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)generation.The resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)capability.The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT.We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model.These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.展开更多
Esophageal squamous cell carcinoma(ESCC)is the most common histological type of esophageal cancer with a poor prognosis.Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC pati...Esophageal squamous cell carcinoma(ESCC)is the most common histological type of esophageal cancer with a poor prognosis.Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC patients.With the advancement of artificial intelligence(AI)technology and the proliferation of medical digital information,AI has demonstrated promising sensitivity and accuracy in assisting precise detection,treatment decision-making,and prognosis assessment of ESCC.It has become a unique opportunity to enhance comprehen-sive clinical management of ESCC in the era of precision oncology.This review examines how AI is applied to the diagnosis,treatment,and prognosis assessment of ESCC in the era of precision oncology,and analyzes the challenges and potential opportunities that AI faces in clinical translation.Through insights into future prospects,it is hoped that this review will contribute to the real-world application of AI in future clinical settings,ultimately alleviating the disease burden caused by ESCC.展开更多
Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resist...Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise treatment.Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological memory.Multiple conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains unsatisfactory.Compared with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer.This review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.展开更多
IntroductionThe UK-ROX trial by Martin et al.[1] represents an important contribution to the expanding evidence base in oxygen therapy research. This large-scale study, although methodologically rigorous, highlights a...IntroductionThe UK-ROX trial by Martin et al.[1] represents an important contribution to the expanding evidence base in oxygen therapy research. This large-scale study, although methodologically rigorous, highlights a persistent challenge in critical care research: the complexity of studying oxygen therapy across heterogeneous patient populations. Oxygen therapy trials in critical care have predominantly compared conservative oxygen targets (oxygen saturation [SpO₂] 88%–92%) against liberal or usual care approaches (SpO₂ ≥96% or no upper limits) in mechanically ventilated intensive care unit (ICU) patients. Conservative strategies aim to minimize hyperoxia-related toxicity, including oxidative stress and inflammatory responses, while liberal approaches prioritize ensuring adequate tissue oxygen delivery. The sequential research program from ICU-ROX through UK-ROX to the ongoing MEGA-ROX trials – conducted by international collaborative research teams with consistent methodologies – offers crucial insights into both the potential and limitations of universal oxygen therapy protocols, while revealing opportunities for personalized therapeutic approaches.展开更多
Pancreatic cancer has a poor prognosis. Current therapies for pancreatic cancer have limited effects. In the past decade, precision medicine has shown great potential for clinical applications. In this review, differe...Pancreatic cancer has a poor prognosis. Current therapies for pancreatic cancer have limited effects. In the past decade, precision medicine has shown great potential for clinical applications. In this review, different strategies for applying precision medicine to the treatment of pancreatic cancer are described.展开更多
Advances in the identification of molecular biomarkers and the development of targeted therapies have enhanced the prognosis of patients with advanced gastric cancer.Several established biomarkers have been widely int...Advances in the identification of molecular biomarkers and the development of targeted therapies have enhanced the prognosis of patients with advanced gastric cancer.Several established biomarkers have been widely integrated into routine clinical diagnostics of gastric cancer to guide personalized treatment.Human epidermal growth factor receptor 2(HER2)was the first molecular biomarker to be used in gastric cancer with trastuzumab being the first approved targeted therapy for HER2-positive gastric cancer.Programmed death-ligand 1 positivity and microsatellite instability can guide the use of immunotherapies,such as pembrolizumab and nivolumab.More recently,zolbetuximab has been approved for patients with claudin 18.2-positive diseases in some countries.More targeted therapies,including savolitinib for MET-positive patients,are currently under clinical investigation.However,the clinical application of these diagnostic approaches could be hampered by many existing challenges,including invasive and costly sampling methods,variability in immunohistochemistry interpretation,high costs and long turnaround times for next-generation sequencing,the absence of standardized and clinically validated diagnostic cut-off values for some biomarkers,and tumor heterogeneity.Novel testing and analysis techniques,such as artificial intelligence-assisted image analysis and multiplex immunohistochemistry,and emerging therapeutic strategies,including combination therapies that integrate immune checkpoint inhibitors with targeted therapies,offer potential solutions to some of these challenges.This article reviews recent progress in gastric cancer testing,outlines current challenges,and explores future directions for biomarker testing and targeted therapy for gastric cancer.展开更多
Drug development and precision therapy are core technologies in the biopharmaceutical field.In the traditional paradigm,new drug development relies on validation through animal testing and clinical trials-a process th...Drug development and precision therapy are core technologies in the biopharmaceutical field.In the traditional paradigm,new drug development relies on validation through animal testing and clinical trials-a process that requires a decade of testing and costs over two billion dollars[1].Although animal testing has long served as the standard approach for evaluating drug efficacy and toxicity,its predictive accuracy for human responses remains limited due to translational barriers arising from interspecies physiological differences[2].Despite passing animal testing,only about 12%of drug candidates proceed to preclinical trials,and fewer than 11.7%gain final approval[3].展开更多
Colorectal cancer(CRC)is the third most prevalent malignancy worldwide and the second leading cause of cancer-related mortality.Its global incidence increases annually,with most patients diagnosed at advanced stages.D...Colorectal cancer(CRC)is the third most prevalent malignancy worldwide and the second leading cause of cancer-related mortality.Its global incidence increases annually,with most patients diagnosed at advanced stages.Despite substantial advancements in chemotherapy,radiotherapy,immune therapy,and targeted therapy,surgical treatment remains the mainstay for CRC management.Particularly,surgery is most effective for managing early-stage and locally advanced cancers.CRC surgery has evolved from conventional subtractive surgery to modern minimally invasive and precision-based techniques.Additionally,CRC treatment strategies have expanded from a single surgical therapy to a multimodal integrated system encompassing endoscopic therapy,perioperative therapy,molecular targeted therapy,and immunotherapy.This review elucidates the evolution of CRC surgical treatment,describing its transition from early palliative surgery to radical surgery,and,finally,to functional surgery,minimally invasive surgical techniques,and personalized treatment.It reflects the transformation in CRC treatment from simplistic to complex,from generalized to precise,and from singular to comprehensive techniques,providing a holistic perspective on advancements in CRC surgical treatment.展开更多
Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce dr...Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce drug resistance or recurrence.Patientderived xenograft(PDX)models are widely used to simulate tumor progression and drug responses,serving as translational tools for precision medicine.This study aimed to establish drug-resistant OSCC PDX models.Human OSCC tissues were transplanted into immunodeficient mice and passaged(P1–P2).At P2(tumor volume:40–80 mm^(3)),mice received cisplatin(1 mg/kg,three times/week)with cetuximab(1 mg/kg,weekly),GSK690693(10 mg/kg,five times/week),or rapamycin(4 mg/kg,five times/week).PDX tissues from groups with less-therapeutic response(manifested as larger tumor volumes)were serially passaged to assess treatment efficacy.Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin–eosin(HE)and immunohistochemical staining after one additional passage and retreatment.Results demonstrated that successive passaging accelerates tumor growth.First-generation treatments showed universal sensitivity.At P2,cisplatin–cetuximab and rapamycin groups remained sensitive,whereas GSK690693 efficacy declined.Continued passaging of GSK690693-treated tumors confirmed resistance,as evidenced by exhibiting enhanced malignant characteristics at histological level.The GSK690693-resistant model was established first,whereas resistant models of other treatment groups were established according to similar protocols.These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution,enabling the development of drug-resistant OSCC models.This study can offer methodological insights for precision therapy of OSCC.展开更多
Triple-negative breast cancer(TNBC)is a highly heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor re...Triple-negative breast cancer(TNBC)is a highly heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression.Due to the lack of specific molecular targets,TNBC does not respond to conventional hormone or HER2-targeted therapies,posing a major challenge in breast cancer treatment.In recent years,molecular biomarkers have shown significant promise in the diagnosis,prognosis,and personalized treatment of TNBC.In-depth investigation of these biomarkers may lead to the development of more effective diagnostic and therapeutic strategies,ultimately improving patient outcomes.This review focuses on recent research progress concerning key molecular biomarkers in TNBC and explores their potential clinical applications,aiming to provide a theoretical basis for the advancement of precision therapy in TNBC.展开更多
Transplant rejection remains a leading cause of graft failure after organ transplantation.Current immunosuppressive therapies can reduce acute rejection,but their lack of specificity often leads to systemic side effec...Transplant rejection remains a leading cause of graft failure after organ transplantation.Current immunosuppressive therapies can reduce acute rejection,but their lack of specificity often leads to systemic side effects and long-term complications.Therefore,novel strategies for localized and durable immune regulation are urgently needed.Nanomedicine offers a promising approach by enabling the precise delivery of therapeutic agents to specific cells or tissues involved in the rejection process.Through rational design,nanoparticles can be engineered to carry immunosuppressive molecules and selectively target transplanted organs,immune organs such as lymph nodes and spleen,or key immune cells,including dendritic cells,macrophages,and T lymphocytes.These delivery systems improve drug bioavailability,reduce off-target effects,and allow controlled or responsive drug release in complex immune environments.In this review,we summarize recent advances in nanoparticle-based interventions for transplant rejection.We discuss the design and classification of nanoparticles,delivery strategies tailored to different graft types,and therapeutic mechanisms targeting various stages and components of the immune response.Examples of both systemic and local administration routes are presented,demonstrating the versatility of nanomedicine in addressing diverse clinical scenarios.Despite encouraging progress in preclinical studies,several challenges continue to limit clinical translation.These include variability in nanoparticle behavior across species,difficulties in large-scale manufacturing,and the lack of standardized regulatory frameworks.Continued efforts in materials innovation,biological validation,and interdisciplinary collaboration are essential to fully realize the clinical potential of nanomedicine in transplantation.展开更多
基金financially supported by the National Natural Science Foundation of China(Grants 52172276)fund from Anhui Provincial Institute of Translational Medicine(2021zhyx-B15)。
文摘Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential.These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature.Inspired by their unique properties,thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine.In this review,the state-of-theart developments in thermosensitive hydrogels for precision therapy are investigated,which covers from the thermo-gelling mechanisms and main components to biomedical applications,including wound healing,anti-tumor activity,osteogenesis,and periodontal,sinonasal and ophthalmic diseases.The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.
基金supported by the Chinese Academy of Medical Sciences(Grant No.2021RU002)Beijing Natural Science Foundation(Grant No.Z240013)+2 种基金National Natural Science Foundation of China(Grant Nos.82450111,82388102,82373416,and 92259303)Beijing Research Ward Excellence Program(Grant Nos.BRWEP2024W034080200 and BRWEP2024W034080204)Peking University People’s Hospital Research and Development Funds(Grant No.RZG2024-02).
文摘Organoids are three-dimensional stem cell-derived models that offer a more physiologically relevant representation of tumor biology compared to traditional two-dimensional cell cultures or animal models.Organoids preserve the complex tissue architecture and cellular diversity of human cancers,enabling more accurate predictions of tumor growth,metastasis,and drug responses.Integration with microfluidic platforms,such as organ-on-a-chip systems,further enhances the ability to model tumor-environment interactions in real-time.Organoids facilitate in-depth exploration of tumor heterogeneity,molecular mechanisms,and the development of personalized treatment strategies when coupled with multi-omics technologies.Organoids provide a platform for investigating tumor-immune cell interactions,which aid in the design and testing of immune-based therapies and vaccines.Taken together,these features position organoids as a transformative tool in advancing cancer research and precision medicine.
基金This study was supported by grants from National Natural Science Foundation of China(Nos.81902784,82273320,and 81771086)the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-5-004)+1 种基金the Fund of Sichuan Provincial Department of Science and Technology(Nos.2022YFSY0058,2022YFS0039,and 2022YFS0003)the Research and Develop Program,West China Hospital of Stomatology,Sichuan University(Nos.LCYJ2023-DL-2 and RCDWJS2020-20).
文摘Background:Oral squamous cell carcinoma(OSCC)is a prevalent type of cancer with a high mortality rate in its late stages.One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor(EGFR)inhibitors.Therefore,it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy.Methods:To evaluate the efficacy of the combination of the Ca^(2+)/calmodulin-dependent protein kinase II(CAMK2)inhibitor KN93 and EGFR inhibitors,we performed in vitro and in vivo experiments using two FAT atypical cadherin 1(FAT1)-deficient(SCC9 and SCC25)and two FAT1 wild-type(SCC47 and HN12)OSCC cell lines.We assessed the effects of EGFR inhibitors(afatinib or cetuximab),KN93,or their combination on the malignant phenotype of OSCC in vivo and in vitro.The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2(SOX2)were analyzed.Changes in the yes-associated protein 1(YAP1)protein were characterized.Moreover,we analyzed mitochondrial dysfunction.Besides,the effects of combination therapy on mitochondrial dynamics were also evaluated.Results:OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment.The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation,survival,and migration of FAT1-mutated OSCC cells and suppressed tumor growth in vivo.Mechanistically,combination therapy enhanced the therapeutic sensitivity of FAT1-mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins.Furthermore,combination therapy induced reactive oxygen species(ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics,ultimately resulting in tumor suppression.Conclusion:Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
基金supported by the National Natural Science Foundation of China(No.32271470).
文摘Multicellular three-dimensional(3D)bioprinting technology,a pivotal in vitro approach in tissue engineering and disease modeling,enables the co-culture of multiple cell populations within 3D architectures while preserving physiological interactions(1).This strategy facilitates the precise simulation of human histogenesis and pathogenesis through four principal modalities:organoid-based systems that recapitulate tissue self-organization,air-liquid interface(ALI)platforms facilitating epithelial-mesenchymal crosstalk analysis,3D microfluidic devices for spatiotemporal control of biomolecular gradients,and bioprinting techniques achieving micron-level spatial patterning of heterogeneous cells(2).Each modality addresses distinct experimental demands in reconstructing multicellular microenvironments,collectively enhancing the fidelity of drug screening and advancing mechanobiological research.
基金supported by the National Natural Science Foundation of China(Nos.82272847,82304417,82303529,82171333)China Postdoctoral Science Foundation(Nos.2023TQ0307,2023M743231,2023M730971)+2 种基金Science and Technology Project of Henan Province(No.242102311204)Postdoctoral Fellowship Program of CPSF(No.GZB20230675)Modern Analysis and Computer Center of Zhengzhou University.
文摘Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through the harsh gastrointestinal environment and intestinal mucus barrier.To overcome the gastrointestinal barriers for oral drug delivery mentioned above,a“spore-like”oral nanodrug delivery platform(Cur/COS/SC NPs)has been developed.Firstly,chitooligosaccharides(COS)are encapsulated on the surface of Curcumin nanoparticles(Cur NPs)to form carrier-free nanoparticles(Cur/COS NPs).Subsequently,inspired by the natural high resistance of spore coat(SC),SC is chosen as the“protective umbrella”to encapsulate Cur/COS NPs for precision targeted therapy of IBD.After oral administration,SC can effectively protect NPs through the rugged gastrointestinal environment and exhibit excellent intestinal mucus penetration characteristics.Moreover,the negatively-charged Cur/COS/SC NPs specifically target positivelycharged inflamed colon via electrostatic interactions.It is demonstrated that Cur/COS/SC NPs can promote the expression of tight junction proteins,inhibit aberrant activation of the Toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB(TLR4/MyD88/NF-κB)signaling pathway,and downregulate the levels of pro-inflammatory factors,exhibiting excellent anti-inflammatory effects.Notably,it is found that Cur/COS/SC NPs can significantly increase the richness and diversity of gut microbiota,and restore the homeostasis of gut microbiota by inhibiting pathogenic bacteria and promoting probiotics.Hence,Cur/COS/SC NPs provide a safe,efficient,and feasible new strategy for IBD treatment.
文摘The 2024 development of a precision-engineered retrotransposon system marked a significant milestone in mammalian genome-editing research.As appeared in the July 8 issue of Cell,this methodological breakthrough established a novel framework for site-specific gene delivery through repurposing ancient viral tools.
文摘BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.
文摘Precision medicine aims to identify the right drug, for the right patient, at the right dose, at the right time, which is particularly important in cancer therapy. Problems such as the variability of treatment response and resistance to medication have been longstanding challenges in oncology, especially for development of new medications. Solid tumors, unlike hematologic malignancies or brain tumors, are remarkably diverse in their cellular origins and developmental timing. The ability of next-generation sequencing(NGS) to analyze the comprehensive landscape of genetic alterations brings promises to diseases that have a highly complex and heterogeneous genetic composition such as cancer. Here we provide an overview of how NGS is able to facilitate precision medicine and change the paradigm of cancer therapy, especially for solid tumors, through technical advancements, molecular diagnosis, response monitoring and clinical trials.
文摘Ovarian cancer is one of the most common malignant tumors in female reproductive organs.Due to the lack of effective screening and early diagnosis methods,the vast majority of patients with ovarian cancer are in advanced stages once diagnosed.Precision therapy mainly includes immunotherapy,targeted therapy,biological therapy,and gene therapy.At present,precision therapy is increasingly used in the clinical treatment of ovarian cancer due to its advantages,such as fewer side effects and a high degree of killing.This article summarizes the recent advances in the precise treatment of ovarian cancer.
基金supported by the National Natural Science Foundation of China(Nos.82102915,22074043 and U22A20328)Lingang Laboratory(No.LG-QS-202206-04)+1 种基金China Postdoctoral Science Foundation(No.2021M700157)Shanghai Post-Doctoral Excellence Program(No.2021424).
文摘Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood circulation.To address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors.These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)generation.The resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)capability.The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT.We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model.These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.
文摘Esophageal squamous cell carcinoma(ESCC)is the most common histological type of esophageal cancer with a poor prognosis.Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC patients.With the advancement of artificial intelligence(AI)technology and the proliferation of medical digital information,AI has demonstrated promising sensitivity and accuracy in assisting precise detection,treatment decision-making,and prognosis assessment of ESCC.It has become a unique opportunity to enhance comprehen-sive clinical management of ESCC in the era of precision oncology.This review examines how AI is applied to the diagnosis,treatment,and prognosis assessment of ESCC in the era of precision oncology,and analyzes the challenges and potential opportunities that AI faces in clinical translation.Through insights into future prospects,it is hoped that this review will contribute to the real-world application of AI in future clinical settings,ultimately alleviating the disease burden caused by ESCC.
基金supported by the National Natural Science Foundation of China(31970696,81502975,82188102,and 81830089)Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR22H160010)+2 种基金National Key Research and Development Program of China(2019YFC1316000)Zhejiang Provincial Key Research and Development Program(2019C03019)Zhejiang Provincial College Student Science and Technology Innovation Activity Plan-College Student Innovation and Entrepreneurship Incubation Program(Young Talent Program)(2022R40122)
文摘Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and microenvironment.Conventional therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise treatment.Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological memory.Multiple conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains unsatisfactory.Compared with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer.This review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.
文摘IntroductionThe UK-ROX trial by Martin et al.[1] represents an important contribution to the expanding evidence base in oxygen therapy research. This large-scale study, although methodologically rigorous, highlights a persistent challenge in critical care research: the complexity of studying oxygen therapy across heterogeneous patient populations. Oxygen therapy trials in critical care have predominantly compared conservative oxygen targets (oxygen saturation [SpO₂] 88%–92%) against liberal or usual care approaches (SpO₂ ≥96% or no upper limits) in mechanically ventilated intensive care unit (ICU) patients. Conservative strategies aim to minimize hyperoxia-related toxicity, including oxidative stress and inflammatory responses, while liberal approaches prioritize ensuring adequate tissue oxygen delivery. The sequential research program from ICU-ROX through UK-ROX to the ongoing MEGA-ROX trials – conducted by international collaborative research teams with consistent methodologies – offers crucial insights into both the potential and limitations of universal oxygen therapy protocols, while revealing opportunities for personalized therapeutic approaches.
文摘Pancreatic cancer has a poor prognosis. Current therapies for pancreatic cancer have limited effects. In the past decade, precision medicine has shown great potential for clinical applications. In this review, different strategies for applying precision medicine to the treatment of pancreatic cancer are described.
基金support by grants from Capital’s Funds for Health Improvement and Research(Grant No.2024-2-1024)Beijing Natural Science Foundation(Grant No.7232018).
文摘Advances in the identification of molecular biomarkers and the development of targeted therapies have enhanced the prognosis of patients with advanced gastric cancer.Several established biomarkers have been widely integrated into routine clinical diagnostics of gastric cancer to guide personalized treatment.Human epidermal growth factor receptor 2(HER2)was the first molecular biomarker to be used in gastric cancer with trastuzumab being the first approved targeted therapy for HER2-positive gastric cancer.Programmed death-ligand 1 positivity and microsatellite instability can guide the use of immunotherapies,such as pembrolizumab and nivolumab.More recently,zolbetuximab has been approved for patients with claudin 18.2-positive diseases in some countries.More targeted therapies,including savolitinib for MET-positive patients,are currently under clinical investigation.However,the clinical application of these diagnostic approaches could be hampered by many existing challenges,including invasive and costly sampling methods,variability in immunohistochemistry interpretation,high costs and long turnaround times for next-generation sequencing,the absence of standardized and clinically validated diagnostic cut-off values for some biomarkers,and tumor heterogeneity.Novel testing and analysis techniques,such as artificial intelligence-assisted image analysis and multiplex immunohistochemistry,and emerging therapeutic strategies,including combination therapies that integrate immune checkpoint inhibitors with targeted therapies,offer potential solutions to some of these challenges.This article reviews recent progress in gastric cancer testing,outlines current challenges,and explores future directions for biomarker testing and targeted therapy for gastric cancer.
基金supported by the Program of the National Natural Science Foundation of China(Grant Nos.:52435006,and 52275291)the Program for Innovation Team of Shaanxi Province The work was supported by the Program of the National Natural Science Foundation of China(Grant Nos.:52435006,and 52275291)the Program for Innovation Team of Shaanxi Province。
文摘Drug development and precision therapy are core technologies in the biopharmaceutical field.In the traditional paradigm,new drug development relies on validation through animal testing and clinical trials-a process that requires a decade of testing and costs over two billion dollars[1].Although animal testing has long served as the standard approach for evaluating drug efficacy and toxicity,its predictive accuracy for human responses remains limited due to translational barriers arising from interspecies physiological differences[2].Despite passing animal testing,only about 12%of drug candidates proceed to preclinical trials,and fewer than 11.7%gain final approval[3].
基金Supported by Postgraduate Practice Innovation Program of Jiangsu Province,No.KYCX23_3621.
文摘Colorectal cancer(CRC)is the third most prevalent malignancy worldwide and the second leading cause of cancer-related mortality.Its global incidence increases annually,with most patients diagnosed at advanced stages.Despite substantial advancements in chemotherapy,radiotherapy,immune therapy,and targeted therapy,surgical treatment remains the mainstay for CRC management.Particularly,surgery is most effective for managing early-stage and locally advanced cancers.CRC surgery has evolved from conventional subtractive surgery to modern minimally invasive and precision-based techniques.Additionally,CRC treatment strategies have expanded from a single surgical therapy to a multimodal integrated system encompassing endoscopic therapy,perioperative therapy,molecular targeted therapy,and immunotherapy.This review elucidates the evolution of CRC surgical treatment,describing its transition from early palliative surgery to radical surgery,and,finally,to functional surgery,minimally invasive surgical techniques,and personalized treatment.It reflects the transformation in CRC treatment from simplistic to complex,from generalized to precise,and from singular to comprehensive techniques,providing a holistic perspective on advancements in CRC surgical treatment.
基金National Natural Science Foundation of China,Grant/Award Number:82173399Young Elite Scientists Sponsorship Program by CAST,Grant/Award Number:2022QNRC001+2 种基金Beijing Natural Science Foundation,Grant/Award Number:7252096Beijing Natural Science Foundation-Haidian Original Innovation Joint Fund Project,Grant/Award Number:L222145CAMS&Comparative Medicine Center,PUMC (IACUC approval number:QC24002)
文摘Oral squamous cell carcinoma(OSCC)constitutes 90%of oral tumors.Advanced cases severely impair patients'life quality of life due to anatomical location and limited therapies.Conventional treatments often induce drug resistance or recurrence.Patientderived xenograft(PDX)models are widely used to simulate tumor progression and drug responses,serving as translational tools for precision medicine.This study aimed to establish drug-resistant OSCC PDX models.Human OSCC tissues were transplanted into immunodeficient mice and passaged(P1–P2).At P2(tumor volume:40–80 mm^(3)),mice received cisplatin(1 mg/kg,three times/week)with cetuximab(1 mg/kg,weekly),GSK690693(10 mg/kg,five times/week),or rapamycin(4 mg/kg,five times/week).PDX tissues from groups with less-therapeutic response(manifested as larger tumor volumes)were serially passaged to assess treatment efficacy.Tumor tissues with diminished drug sensitivity underwent histopathological analysis and identified stability of their tumor characteristics using hematoxylin–eosin(HE)and immunohistochemical staining after one additional passage and retreatment.Results demonstrated that successive passaging accelerates tumor growth.First-generation treatments showed universal sensitivity.At P2,cisplatin–cetuximab and rapamycin groups remained sensitive,whereas GSK690693 efficacy declined.Continued passaging of GSK690693-treated tumors confirmed resistance,as evidenced by exhibiting enhanced malignant characteristics at histological level.The GSK690693-resistant model was established first,whereas resistant models of other treatment groups were established according to similar protocols.These findings suggest that sequential passaging and drug exposure in PDX models recapitulated clinical tumor evolution,enabling the development of drug-resistant OSCC models.This study can offer methodological insights for precision therapy of OSCC.
基金supported by the Science and Technology Research Project of Henan Province(Grant No.252102311028)titled“Study on ECT2 as a Potential Molecular Marker and Therapeutic Target in the Diagnosis and Treatment of Breast Cancer.”。
文摘Triple-negative breast cancer(TNBC)is a highly heterogeneous and aggressive subtype of breast cancer characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression.Due to the lack of specific molecular targets,TNBC does not respond to conventional hormone or HER2-targeted therapies,posing a major challenge in breast cancer treatment.In recent years,molecular biomarkers have shown significant promise in the diagnosis,prognosis,and personalized treatment of TNBC.In-depth investigation of these biomarkers may lead to the development of more effective diagnostic and therapeutic strategies,ultimately improving patient outcomes.This review focuses on recent research progress concerning key molecular biomarkers in TNBC and explores their potential clinical applications,aiming to provide a theoretical basis for the advancement of precision therapy in TNBC.
基金supported by the Natural Science Foundation of China(82151316,82171964,82230066,82202234,12326619)the Natural Science Foundation of Wuhan(2024040801020350)the Natural Science Foundation of Hubei(2021CFA046 and 2023AFB753).
文摘Transplant rejection remains a leading cause of graft failure after organ transplantation.Current immunosuppressive therapies can reduce acute rejection,but their lack of specificity often leads to systemic side effects and long-term complications.Therefore,novel strategies for localized and durable immune regulation are urgently needed.Nanomedicine offers a promising approach by enabling the precise delivery of therapeutic agents to specific cells or tissues involved in the rejection process.Through rational design,nanoparticles can be engineered to carry immunosuppressive molecules and selectively target transplanted organs,immune organs such as lymph nodes and spleen,or key immune cells,including dendritic cells,macrophages,and T lymphocytes.These delivery systems improve drug bioavailability,reduce off-target effects,and allow controlled or responsive drug release in complex immune environments.In this review,we summarize recent advances in nanoparticle-based interventions for transplant rejection.We discuss the design and classification of nanoparticles,delivery strategies tailored to different graft types,and therapeutic mechanisms targeting various stages and components of the immune response.Examples of both systemic and local administration routes are presented,demonstrating the versatility of nanomedicine in addressing diverse clinical scenarios.Despite encouraging progress in preclinical studies,several challenges continue to limit clinical translation.These include variability in nanoparticle behavior across species,difficulties in large-scale manufacturing,and the lack of standardized regulatory frameworks.Continued efforts in materials innovation,biological validation,and interdisciplinary collaboration are essential to fully realize the clinical potential of nanomedicine in transplantation.
