The complex pathophysiology and diverse manifestations of esophageal disorders pose challenges in clinical practice,particularly in achieving accurate early diagnosis and risk stratification.While traditional approach...The complex pathophysiology and diverse manifestations of esophageal disorders pose challenges in clinical practice,particularly in achieving accurate early diagnosis and risk stratification.While traditional approaches rely heavily on subjective interpretations and variable expertise,machine learning(ML)has emerged as a transformative tool in healthcare.We conducted a comprehensive review of published literature on ML applications in esophageal diseases,analyzing technical approaches,validation methods,and clinical outcomes.ML demonstrates superior performance:In gastroesophageal reflux disease,ML models achieve 80%-90%accuracy in potential of hydrogen-impedance analysis and endoscopic grading;for Barrett’s esophagus,ML-based approaches show 88%-95% accuracy in invasive diagnostics and 77%-85% accuracy in non-invasive screening.In esophageal cancer,ML improves early detection and survival prediction by 6%-10% compared to traditional methods.Novel applications in achalasia and esophageal varices demonstrate promising results in automated diagnosis and risk stratification,with accuracy rates exceeding 85%.While challenges persist in data standardization,model interpretability,and clinical integration,emerging solutions in federated learning and explainable artificial intelligence offer promising pathways forward.The continued evolution of these technologies,coupled with rigorous validation and thoughtful implementation,may fundamentally transform our approach to esophageal disease management in the era of precision medicine.展开更多
Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patien...Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.展开更多
With the significant advances in cancer genomics using next-generation sequencing technologies,genomic and molecular profilingbased precision medicine is used as a part of routine clinical test for guiding and selecti...With the significant advances in cancer genomics using next-generation sequencing technologies,genomic and molecular profilingbased precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients.Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed,the clinical application of such information is still limited to a small proportion of cancer patients.In this review,we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information.Cancer immunotherapies,including immune checkpoint inhibitors,would be one of the potential approaches to apply the results of genomic sequencing most effectively.Highly cancer-specific antigens derived from somatic mutations,the so-called neoantigens,occurring in individual cancers have been in focus recently.Cancer immunotherapies,which target neoantigens,could lead to a precise treatment for cancer patients,despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients.Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.展开更多
Background:Macrovascular invasion(MaVI)occurs in nearly half of hepatocellular carcinoma(HCC)patients at diagnosis or during follow-up,which causes severe disease deterioration,and limits the possibility of surgical a...Background:Macrovascular invasion(MaVI)occurs in nearly half of hepatocellular carcinoma(HCC)patients at diagnosis or during follow-up,which causes severe disease deterioration,and limits the possibility of surgical approaches.This study aimed to investigate whether computed tomography(CT)-based radiomics analysis could help predict development of MaVI in HCC.Methods:A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups.CT-based radiomics signature was built via multi-strategy machine learning methods.Afterwards,MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model(CRIM,clinical-radiomics integrated model)via random forest modeling.Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development.Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development,progression-free survival(PFS),and overall survival(OS)based on the selected risk factors.Results:The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors(P<0.001).CRIM could predict MaVI with satisfactory areas under the curve(AUC)of 0.986 and 0.979 in the training(n=154)and external validation(n=72)datasets,respectively.CRIM presented with excellent generalization with AUC of 0.956,1.000,and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory.Peel9_fos_InterquartileRange[hazard ratio(HR)=1.98;P<0.001]was selected as the independent risk factor.The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development(P<0.001),PFS(P<0.001)and OS(P=0.002).Conclusions:The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.展开更多
The major challenges of the "brain disorders" field-dementia,schizophrenia,other neuropsychiatric disorders-are that these are defined by clinical phenotypes whose underlying biology is poorly understood.The...The major challenges of the "brain disorders" field-dementia,schizophrenia,other neuropsychiatric disorders-are that these are defined by clinical phenotypes whose underlying biology is poorly understood.There is great variability in definition,prognosis,trajectory,and treatment response indicating that the next step is defining subgroups by combining clinical and biologic information at the level of the individual.These challenges are especially relevant and urgent in the case of dementia and related disorders.展开更多
Reproductive hormones associated with the hypothalamic-pituitary-gonadal(HPG)axis are closely linked to bone homeostasis.In this study,we demonstrate that Gonadotropin inhibitory hormone(GnIH,one of the key reproducti...Reproductive hormones associated with the hypothalamic-pituitary-gonadal(HPG)axis are closely linked to bone homeostasis.In this study,we demonstrate that Gonadotropin inhibitory hormone(GnIH,one of the key reproductive hormones upstream of the HPG axis)plays an indispensable role in regulating bone homeostasis and maintaining bone mass.We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density(BMD)in mice primarily by enhancement of osteoclast activation in vivo and in vitro.Mechanistically,GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT,MAPK,NF-κB and Nfatc1 signaling pathways.Furthermore,GnIH treatment was able to alleviate bone loss in aging,ovariectomy(OVX)or LPS-induced mice.Moreover,the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss.In humans,serum GnIH increases and bone resorption markers decrease after green light exposure.Therefore,our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.展开更多
BACKGROUND Emerging evidence indicates that hypoxic preconditioning boosts the antioxidant and anti-apoptotic capacities of mesenchymal stem cell-derived exosomes;however,the specific mechanisms remain incompletely el...BACKGROUND Emerging evidence indicates that hypoxic preconditioning boosts the antioxidant and anti-apoptotic capacities of mesenchymal stem cell-derived exosomes;however,the specific mechanisms remain incompletely elucidated.This study explored the impact of hypoxia-preconditioned mesenchymal stem cell-derived exosomes(hypo-Exos)vs normoxic counterparts on the apoptotic response in cardiomyocytes triggered by oxidative stress.AIM To determine whether and how hypoxic preconditioning augments the cardioprotective efficacy of hypo-Exos against oxidative stress-induced cardiomyocyte apoptosis.METHODS H9C2 cardiomyocytes were treated with hydrogen peroxide(H2O2)to induce oxidative injury.Assessments of cell viability,oxidative biomarkers,and apoptotic activity were conducted to evaluate the therapeutic efficacy of hypo-Exos and normoxic counterparts.High-throughput sequencing was performed to identify potential target microRNAs(miRNAs).Luciferase reporter assays were conducted to confirm selected miRNAs binding to target genes.Hypo-Exos loaded with selected miRNAs antagomirs or negative controls were administered to H2O2-treated H9C2 cells to validate the downstream signaling pathways involved.RESULTS Hypo-Exos significantly enhanced cell viability,reduced oxidative stress,and inhibited apoptosis of cardiomyocytes.Hypoxic preconditioning significantly increased the expression of exosomal miR-486-5p,which directly targeted the phosphatase and tensin homolog.Additionally,hypo-Exos markedly activated the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)pathway.Moreover,deletion of miR-486-5p in hypo-Exos counteracted the anti-apoptotic effects and suppressed PI3K/Akt pathway activation.CONCLUSION Hypoxic preconditioning augments anti-apoptotic properties of exosomes,primarily via miR-486-5p upregulation,which mediates its function by modulating the phosphatase and tensin homolog/PI3K/Akt axis.展开更多
The Jhelum River Basin in Pakistan has experienced recurrent and severe flooding over the past several decades,leading to substantial economic losses,infrastructure damage,and socio-environmental disruptions.This stud...The Jhelum River Basin in Pakistan has experienced recurrent and severe flooding over the past several decades,leading to substantial economic losses,infrastructure damage,and socio-environmental disruptions.This study uses multi-temporal satellite remote sensing data with historical hydrological records to map the spatial and temporal dynamics of major flood events occurring between 1988 and 2019.By utilizing satellite imagery from Landsat 5,Landsat 8,and Sentinel-2,key flood events were analyzed through the application of water indices such as the Normalized DifferenceWater Index(NDWI)and theModified NDWI(MNDWI)to delineate flood extents.Historical discharge data from key hydrological control points,including Mangla Dam and Rasul Barrage,were incorporated to validate and interpret flood intensity and inundation patterns.Flood footprints were extracted and mapped using preand post-flood images in Google Earth Engine,while land use and land cover(LULC)analysis revealed a consistent increase in built-up areas and a corresponding decline in vegetative cover in flood-prone tehsils from 1988 to 2023.Findings indicated that the flood years 1992 and 1997were themost catastrophic,with over 180 km2 of land submerged.A substantial proportion of inundated zones consisted of agricultural land and low-lying urban settlements,underscoring the vulnerability of these areas.This study proved the effectiveness of integrating satellite imagery and historical hydrological data for spatio-temporal flood monitoring and provides essential insights for future flood risk assessment and the development of site-specific mitigation strategies in vulnerable areas of the Jhelum River Basin.展开更多
Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is no...Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is not fully understood.This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC.Methods:Tissue immunohistochemistry,TCGA,and GEO databases were used to analyze the expression of YBX1 in ICC.The expression of YBX1 was silenced and overexpressed in cell lines.Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses.Actinomycin D,RNA immunoprecipitation,and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes.Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC.Results:The research findings indicated that ICC exhibited high levels of YBX1 expression,which was strongly associated with unfavorable outcomes.YBX1 promoted tumor progression by suppressing antitumor T-cell responses.YBX1 enhanced signal transducer and activator of transcription 1(STAT1)translation by serving as a 5-methylated cytosine(m5C)reader and activating the STAT1/PD-L1 pathway.Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1,STAT1,and PD-L1 expression.Conclusions:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.展开更多
BACKGROUND Diabetic retinopathy(DR)is one of the major eye diseases contributing to blindness worldwide.Endoplasmic reticulum(ER)stress in retinal cells is a key factor leading to retinal inflammation and vascular lea...BACKGROUND Diabetic retinopathy(DR)is one of the major eye diseases contributing to blindness worldwide.Endoplasmic reticulum(ER)stress in retinal cells is a key factor leading to retinal inflammation and vascular leakage in DR,but its mechanism is still unclear.AIM To investigate the potential mechanism of LEF1 and related RNAs in DR.METHODS ARPE-19 cells were exposed to high levels of glucose for 24 hours to simulate a diabetic environment.Intraperitoneally injected streptozotocin was used to induce the rat model of DR.The expression levels of genes and related proteins were measured by RT-qPCR and Western blotting;lnc-MGC and miR-495-3p were detected by fluorescent in situ hybridization;CCK-8 and TUNEL assays were used to detect cell viability and apoptosis;enzyme-linked immunosorbent assay was used to detect inflammatory factors;dual-luciferase gene assays were used to verify the targeting relationship;and the retina was observed by HE staining.RESULTS LEF1 and lnc-MGC have binding sites,and lnc-MGC can regulate the miR-495-3p/GRP78 molecular axis.In high glucose-treated cells,inflammation was aggravated,the intracellular reactive oxygen species concentration was increased,cell viability was reduced,apoptosis was increased,the ER response was intensified,and ferroptosis was increased.As an ER molecular chaperone,GRP78 regulates the ER and ferroptosis under the targeting of miR-495-3p,whereas inhibiting LEF1 can further downregulate the expression of lnc-MGC,increase the level of miR-495-3p,and sequentially regulate the level of GRP78 to alleviate the occurrence and development of DR.Animal experiments indicated that the knockdown of LEF1 can affect the lnc-MGC/miR-495-3p/GRP78 signaling axis to restrain the progression of DR.CONCLUSION LEF1 knockdown can regulate the miR-495-3p/GRP78 molecular axis through lnc-MGC,which affects ER stress and restrains the progression of DR and ferroptosis in retinal pigment epithelial cells.展开更多
BACKGROUND Some patients with resectable or borderline resectable pancreatic ductal adenocarcinoma(PDAC)may have distant metastases,undetected on preoperative imaging or early recurrence,within 6 months after surgery....BACKGROUND Some patients with resectable or borderline resectable pancreatic ductal adenocarcinoma(PDAC)may have distant metastases,undetected on preoperative imaging or early recurrence,within 6 months after surgery.Occult metastases(OMs)must be accurately predicted to optimize multidisciplinary treatment.AIM To investigate the efficacy of circulating tumor DNA(ctDNA)in predicting OM.METHODS Two Japanese institutions prospectively collected preoperative plasma samples from PDAC patients between July 2019 and September 2021 and evaluated ctDNA using a targeted next-generation sequencing panel covering 52 cancer-related genes.RESULTS Among 135 PDAC patients,38 had OM and 35 were positive for ctDNA.The ctDNA positivity rate was significantly higher in patients with OM than in patients without OM.ctDNA-positive patients had significantly shorter median recurrence-free survival than ctDNA-negative patients.Logistic multivariate regression revealed ctDNA positivity as an independent predictor of OM.CONCLUSION Preoperative ctDNA in resectable PDAC is an independent predictor of OM and indicates poor prognosis following pancreatectomy and may be a useful biomarker in determining multidisciplinary patient care.展开更多
The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV c...The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.展开更多
Background: Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and...Background: Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and HCC development through the gut-liver axis. Data sources: Recently there have been several innovative studies investigating gut microbial dysbiosismediated enhancement of HCC through the gut-liver axis. Literatures from January 1998 to January 2018 were searched in the Pub Med database using the keywords "gut microbiota" and "hepatocellular carcinoma" or "liver cancer", and the results of experimental and clinical studies were analyzed. Results: Gut microbial dysbiosis accompanies the progression of alcoholic liver disease, non-alcoholic fatty liver disease and liver cirrhosis, and promotes HCC progression in an experimental mouse model. The immune system and key factors such as Toll-like receptor 4 are involved in the process. There is evidence for gut microbial dysbiosis in hepatitis virus-related HCC patients. Conclusions: Gut microbial dysbiosis is closely associated with hepatic inflammation disease and HCC through the gut-liver axis. With the enhanced understanding of the interactions between gut microbiota and liver through the gut-liver axis, new treatment strategies for HCC are being developed.展开更多
OBJECTIVE To discover a small-molecule bromodomain-containing protein 4(BRD4)inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer and exploreits potential mech...OBJECTIVE To discover a small-molecule bromodomain-containing protein 4(BRD4)inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer and exploreits potential mechanisms.METHODS BRD4 interactors were analyzed by PPI network prediction and The Cancer Genome Atlas(TCGA)analysis.The interaction between BRD4 and AMPK was confirmed by co-immunoprecipitation assay.Novel BRD4 inhibitors were designed and synthesized based upon pharmacophore analysis of BRD4(1),then screened by antiproliferative activity and Alpha Screen of BRD4(1).The selectivity of the best candidate compound 8f was validated by co-crystallization,FRET assay and co-immuno precipitation assay.The mechanisms of 8f were investigated by fluorescence microscopy,electron microscopy,Western blotting,immunocytochemistry,si RNA and GFP-m RFP-LC3 plasmid transfections,as well as immunohistochemistry and immunofluorescence.Potential mechanisms were discovered by i TRAQ-based proteomics analysis and the therapeutic effect of 8f was assessed by xenograft breast cancer mouse and zebrafish models.RESULTS We identified that BRD4 interacted with AMPK,which was remarkably downregulated in breast cancer.We next designed and synthesized 49 candidate compounds,and eventually discovered a selective small-molecule inhibitor of BRD4(8f).Subsequently,8f was discovered to induce autophagyassociated cell death(ACD)by BRD4-AMPK interaction,and thus activating AMPK-m TOR-ULK1-modulated autophagic pathway in breast cancer cells.Interestingly,the i TRAQ-based proteomics analyses revealed that 8f induced ACD pathways,involved in HMGB1,VDAC1/2 and e EF2.Moreover,8f displayed a therapeutic potential on both xenograft breast cancer mouse and zebrafish models.CONCLUSION We discovered a novel small-molecule inhibitor of BRD4 that induces BRD4-AMPK-modulated ACD in breast cancer,which may provide a candidate drug for future cancer therapy.展开更多
Hepatitis B virus(HBV)has posed a threat to public health,mainly resulting in liver damage.With long-term accumulation of extracellular matrix,patients with chronic hepatitis B are at high risk of developing into live...Hepatitis B virus(HBV)has posed a threat to public health,mainly resulting in liver damage.With long-term accumulation of extracellular matrix,patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma.The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality.With deeper understanding of the bidirectional interaction between the liver and the gut(gut-liver axis),there is a growing consensus that the human health closely relates to the gut microbiota.Supported by animal and human studies,the gut microbiota alters as the HBV-related liver fibrosis initials and progresses,characterized as the decrease of the ratio between“good”and“potentially pathogenic”microbes.When the primary disease is controlled via antiviral treatment,the gut microbiota dysfunction tends to be improved.Conversely,the recovery of gut microbiota can promote the regression of liver fibrosis.Therapeutic strategies targeted on gut microbiota(rifaximin,probiotics,engineered probiotics and fecal microbiota transplantation)have been applied to animal models and patients,obtaining satisfactory results.展开更多
Background:Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related death worldwide.Due to the high prevalence of hepatitis B virus(HBV)infection in China,the incidence of HCC in China is high,and li...Background:Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related death worldwide.Due to the high prevalence of hepatitis B virus(HBV)infection in China,the incidence of HCC in China is high,and liver cirrhosis caused by chronic hepatitis also brings great challenges to treatment.This paper reviewed the latest research progress on minimally invasive treatments for HCC,including percutaneous thermal ablation and new nonthermal ablation techniques,and introduced the principles,advantages,and clinical applications of various therapeutic methods in detail.Data sources:The data of treatments for HCC were systematically collected from the Pub Med,Science Direct,American Chemical Society and Web of Science databases published in English,using“minimally invasive”and“hepatocellular carcinoma”or“liver cancer”as the keywords.Results:Percutaneous thermal ablation is still a first-line strategy for the minimally invasive treatment of HCC.The effect of microwave ablation(MWA)on downgrading treatment before liver transplantation is better than that of radiofrequency ablation(RFA),while RFA is more widely used in the clinical practice.High-intensity focused ultrasound(HIFU)is mainly used for the palliative treatment of advanced liver cancer.Electrochemotherapy(ECT)delivers chemotherapeutic drugs to the target cells while reducing the blood supply around HCC.Irreversible electroporation(IRE)uses a microsecond-pulsed electric field that induces apoptosis and necrosis and triggers a systemic immune response.The nanosecond pulsed electric field(ns PEF)has achieved a good response in the ablation of mice with HCC,but it has not been reported in China for the treatment of human HCC.Conclusions:A variety of minimally invasive treatments provide a sufficient survival advantage for HCC patients.Nonthermal ablation will lead to a new wave with its unique advantage of antitumor recurrence and metastasis.展开更多
Background:microRNA-139(miR-139)is dysregulated in various types of tumors and plays a key role in carcinogenesis.miR-139 may be used as a diagnostic and prognostic biomarker of cancers.However,the data from the liter...Background:microRNA-139(miR-139)is dysregulated in various types of tumors and plays a key role in carcinogenesis.miR-139 may be used as a diagnostic and prognostic biomarker of cancers.However,the data from the literature are not consistent.The present study aimed to verify the prognostic and diagnostic values of miR-139 in solid tumors.Data sources:PubMed,Web of Science and Embase databases were searched and publications from January 2011 to August 2017 were included.We used Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)database to further validate this meta-analysis.Results:Eight individual studies from seven articles were included.Pooled analyses showed that low miR-139 expression was related to worse overall survival(OS)[hazard ratio(HR)=2.27;95%confidence intervals(CI):1.74–2.95;P<0.001]in solid tumors,including hepatocellular carcinoma(HCC)and glioblastoma multiforme(GBM),consisting with the results of TCGA.However,our results of CRC showed that low miR-139 expression was associated with poor OS which was contradictory with the results in TCGA database and need larger samples to validate the phenomenon;whereas for CRC patients,high miR-139 expression predicted poor RFS,which was in good accordance with TCGA results.The results of 27 microarrays from GEO database showed that miR-139 expression levels were lower in tumor tissues compared to adjacent non-tumor tissues or healthy tissues.Decreased miR-139 expression was also significantly correlated with poor differentiation grade(OR=3.57;95%CI:1.44–8.85;P=0.006).However,the combined data indicated that no associations between miR-139 expression and the following parameters such as age(pooled OR=1.50;95%CI:0.69–3.24;P=0.304),gender(pooled OR=0.92;95%CI:0.56–1.51;P=0.738),tumor size(pooled OR=1.51;95%CI:0.69–3.31;P=0.298),late tumor-node-metastasis stage(pooled OR=1.63;95%CI:0.99–2.68;P=0.057)and lymph-node-metastasis(pooled OR=0.66;95%CI:0.34–1.28;P=0.222).Conclusions:Low miR-139 expression was related to poor prognosis in HCC and GBM,which could be regarded as a potential prognostic biomarker.However,its precise functional role in CRC still need to be further investigated through larger samples and multicenter studies.展开更多
Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important...Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.展开更多
The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are s...The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.展开更多
In-season diagnosis of crop nitrogen(N) status is crucial for precision N management. Critical N(N_c) dilution curve and N nutrition index(NNI) have been proposed as effective methods to diagnose N status of different...In-season diagnosis of crop nitrogen(N) status is crucial for precision N management. Critical N(N_c) dilution curve and N nutrition index(NNI) have been proposed as effective methods to diagnose N status of different crops. The N_c dilution curves have been developed for indica rice in the tropical and temperate zones and japonica rice in the subtropical-temperate zone, but they have not been evaluated for short-season japonica rice in Northeast China. The objectives of this study were to evaluate the previously developed N_c dilution curves for rice in Northeast China and to develop a more suitable N_c dilution curve in this region. A total of17 N rate experiments were conducted in Sanjiang Plain, Heilongjiang Province in Northeast China from 2008 to 2013. The results indicated that none of the two previously developed N_c dilution curves was suitable to diagnose N status of the short-season japonica rice in Northeast China. A new N_c dilution curve was developed and can be described by the equation N_c = 27.7 W^(-0.34) if W ≥ 1 Mg dry matter(DM) ha^(-1) or N_c = 27.7 g kg^(-1) DM if W < 1 Mg DM ha^(-1), where W is the aboveground biomass. This new curve was lower than the previous curves. It was validated using a separate dataset, and it could discriminate non-N-limiting and N-limiting nutritional conditions. Additional studies are needed to further evaluate it for diagnosing N status of different rice cultivars in Northeast China and develop efficient non-destructive methods to estimate NNI for practical applications.展开更多
基金Supported by the Central Funds Guiding the Local Science and Technology Development,No.202207AB110017Key Research and Development Program of Yunnan,No.202302AD080004+1 种基金Yunnan Academician and Expert Workstation,No.202205AF150023the Scientific and Technological Innovation Team in Kunming Medical University,No.CXTD202215.
文摘The complex pathophysiology and diverse manifestations of esophageal disorders pose challenges in clinical practice,particularly in achieving accurate early diagnosis and risk stratification.While traditional approaches rely heavily on subjective interpretations and variable expertise,machine learning(ML)has emerged as a transformative tool in healthcare.We conducted a comprehensive review of published literature on ML applications in esophageal diseases,analyzing technical approaches,validation methods,and clinical outcomes.ML demonstrates superior performance:In gastroesophageal reflux disease,ML models achieve 80%-90%accuracy in potential of hydrogen-impedance analysis and endoscopic grading;for Barrett’s esophagus,ML-based approaches show 88%-95% accuracy in invasive diagnostics and 77%-85% accuracy in non-invasive screening.In esophageal cancer,ML improves early detection and survival prediction by 6%-10% compared to traditional methods.Novel applications in achalasia and esophageal varices demonstrate promising results in automated diagnosis and risk stratification,with accuracy rates exceeding 85%.While challenges persist in data standardization,model interpretability,and clinical integration,emerging solutions in federated learning and explainable artificial intelligence offer promising pathways forward.The continued evolution of these technologies,coupled with rigorous validation and thoughtful implementation,may fundamentally transform our approach to esophageal disease management in the era of precision medicine.
基金supported by the Canadian Institutes of Health Research(DFD-181599)the National Institutes of Health(T32AG058527)to RJB and R0190106435 to VM.
文摘Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.
基金This work was partly supported by Japan Agency for Medical Research and Development(Grant Nos.17ck0106364h0003 and 20ck0106543h0001)the Japan Society for the Promotion of Science(Grant No.19H03522).
文摘With the significant advances in cancer genomics using next-generation sequencing technologies,genomic and molecular profilingbased precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients.Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed,the clinical application of such information is still limited to a small proportion of cancer patients.In this review,we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information.Cancer immunotherapies,including immune checkpoint inhibitors,would be one of the potential approaches to apply the results of genomic sequencing most effectively.Highly cancer-specific antigens derived from somatic mutations,the so-called neoantigens,occurring in individual cancers have been in focus recently.Cancer immunotherapies,which target neoantigens,could lead to a precise treatment for cancer patients,despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients.Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.
基金supported by grants from the National Key R&D Program of China(2017YFA0205200,2017YFC1308701,and 2017YFC1309100)National Natural Science Foundation of China(82001917,81930053,81227901,81771924,81501616,81571785,81771957,and 61671449)the Natural Science Foundation of Guangdong Province,China(2016A030311055 and 2016A030313770)。
文摘Background:Macrovascular invasion(MaVI)occurs in nearly half of hepatocellular carcinoma(HCC)patients at diagnosis or during follow-up,which causes severe disease deterioration,and limits the possibility of surgical approaches.This study aimed to investigate whether computed tomography(CT)-based radiomics analysis could help predict development of MaVI in HCC.Methods:A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups.CT-based radiomics signature was built via multi-strategy machine learning methods.Afterwards,MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model(CRIM,clinical-radiomics integrated model)via random forest modeling.Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development.Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development,progression-free survival(PFS),and overall survival(OS)based on the selected risk factors.Results:The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors(P<0.001).CRIM could predict MaVI with satisfactory areas under the curve(AUC)of 0.986 and 0.979 in the training(n=154)and external validation(n=72)datasets,respectively.CRIM presented with excellent generalization with AUC of 0.956,1.000,and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory.Peel9_fos_InterquartileRange[hazard ratio(HR)=1.98;P<0.001]was selected as the independent risk factor.The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development(P<0.001),PFS(P<0.001)and OS(P=0.002).Conclusions:The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.
基金supported by the grant from the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease at Johns Hopkins。
文摘The major challenges of the "brain disorders" field-dementia,schizophrenia,other neuropsychiatric disorders-are that these are defined by clinical phenotypes whose underlying biology is poorly understood.There is great variability in definition,prognosis,trajectory,and treatment response indicating that the next step is defining subgroups by combining clinical and biologic information at the level of the individual.These challenges are especially relevant and urgent in the case of dementia and related disorders.
基金National Key Research and Development Program of China(2023YFB3810200 to J.L.)National Natural Science Foundation of China(92168204,82225030 to J.L.)Fundamental Research Funds for the Central Universities(22120210586 to J.L.)。
文摘Reproductive hormones associated with the hypothalamic-pituitary-gonadal(HPG)axis are closely linked to bone homeostasis.In this study,we demonstrate that Gonadotropin inhibitory hormone(GnIH,one of the key reproductive hormones upstream of the HPG axis)plays an indispensable role in regulating bone homeostasis and maintaining bone mass.We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density(BMD)in mice primarily by enhancement of osteoclast activation in vivo and in vitro.Mechanistically,GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT,MAPK,NF-κB and Nfatc1 signaling pathways.Furthermore,GnIH treatment was able to alleviate bone loss in aging,ovariectomy(OVX)or LPS-induced mice.Moreover,the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss.In humans,serum GnIH increases and bone resorption markers decrease after green light exposure.Therefore,our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.
基金the Precision Medical Center of Nanfang Hospital,with the informed consent of all participants and approved by the Medical Ethics Committee of the hospital(Approval No.NFEC-202110-K17-01).
文摘BACKGROUND Emerging evidence indicates that hypoxic preconditioning boosts the antioxidant and anti-apoptotic capacities of mesenchymal stem cell-derived exosomes;however,the specific mechanisms remain incompletely elucidated.This study explored the impact of hypoxia-preconditioned mesenchymal stem cell-derived exosomes(hypo-Exos)vs normoxic counterparts on the apoptotic response in cardiomyocytes triggered by oxidative stress.AIM To determine whether and how hypoxic preconditioning augments the cardioprotective efficacy of hypo-Exos against oxidative stress-induced cardiomyocyte apoptosis.METHODS H9C2 cardiomyocytes were treated with hydrogen peroxide(H2O2)to induce oxidative injury.Assessments of cell viability,oxidative biomarkers,and apoptotic activity were conducted to evaluate the therapeutic efficacy of hypo-Exos and normoxic counterparts.High-throughput sequencing was performed to identify potential target microRNAs(miRNAs).Luciferase reporter assays were conducted to confirm selected miRNAs binding to target genes.Hypo-Exos loaded with selected miRNAs antagomirs or negative controls were administered to H2O2-treated H9C2 cells to validate the downstream signaling pathways involved.RESULTS Hypo-Exos significantly enhanced cell viability,reduced oxidative stress,and inhibited apoptosis of cardiomyocytes.Hypoxic preconditioning significantly increased the expression of exosomal miR-486-5p,which directly targeted the phosphatase and tensin homolog.Additionally,hypo-Exos markedly activated the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)pathway.Moreover,deletion of miR-486-5p in hypo-Exos counteracted the anti-apoptotic effects and suppressed PI3K/Akt pathway activation.CONCLUSION Hypoxic preconditioning augments anti-apoptotic properties of exosomes,primarily via miR-486-5p upregulation,which mediates its function by modulating the phosphatase and tensin homolog/PI3K/Akt axis.
文摘The Jhelum River Basin in Pakistan has experienced recurrent and severe flooding over the past several decades,leading to substantial economic losses,infrastructure damage,and socio-environmental disruptions.This study uses multi-temporal satellite remote sensing data with historical hydrological records to map the spatial and temporal dynamics of major flood events occurring between 1988 and 2019.By utilizing satellite imagery from Landsat 5,Landsat 8,and Sentinel-2,key flood events were analyzed through the application of water indices such as the Normalized DifferenceWater Index(NDWI)and theModified NDWI(MNDWI)to delineate flood extents.Historical discharge data from key hydrological control points,including Mangla Dam and Rasul Barrage,were incorporated to validate and interpret flood intensity and inundation patterns.Flood footprints were extracted and mapped using preand post-flood images in Google Earth Engine,while land use and land cover(LULC)analysis revealed a consistent increase in built-up areas and a corresponding decline in vegetative cover in flood-prone tehsils from 1988 to 2023.Findings indicated that the flood years 1992 and 1997were themost catastrophic,with over 180 km2 of land submerged.A substantial proportion of inundated zones consisted of agricultural land and low-lying urban settlements,underscoring the vulnerability of these areas.This study proved the effectiveness of integrating satellite imagery and historical hydrological data for spatio-temporal flood monitoring and provides essential insights for future flood risk assessment and the development of site-specific mitigation strategies in vulnerable areas of the Jhelum River Basin.
基金supported by a grant from the National Natural Science Foundation of China(No.82070643)。
文摘Background:Intrahepatic cholangiocarcinoma(ICC)is the second most frequent primary liver cancer.The involvement of Y-box binding protein 1(YBX1)in tumor advancement is well-documented.However,its function in ICC is not fully understood.This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC.Methods:Tissue immunohistochemistry,TCGA,and GEO databases were used to analyze the expression of YBX1 in ICC.The expression of YBX1 was silenced and overexpressed in cell lines.Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses.Actinomycin D,RNA immunoprecipitation,and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes.Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC.Results:The research findings indicated that ICC exhibited high levels of YBX1 expression,which was strongly associated with unfavorable outcomes.YBX1 promoted tumor progression by suppressing antitumor T-cell responses.YBX1 enhanced signal transducer and activator of transcription 1(STAT1)translation by serving as a 5-methylated cytosine(m5C)reader and activating the STAT1/PD-L1 pathway.Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1,STAT1,and PD-L1 expression.Conclusions:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.
基金Supported by Science and Technology Program of Yunnan Provincial Department of Science and Technology-Basic Research Program,No.202301BA070001-025.
文摘BACKGROUND Diabetic retinopathy(DR)is one of the major eye diseases contributing to blindness worldwide.Endoplasmic reticulum(ER)stress in retinal cells is a key factor leading to retinal inflammation and vascular leakage in DR,but its mechanism is still unclear.AIM To investigate the potential mechanism of LEF1 and related RNAs in DR.METHODS ARPE-19 cells were exposed to high levels of glucose for 24 hours to simulate a diabetic environment.Intraperitoneally injected streptozotocin was used to induce the rat model of DR.The expression levels of genes and related proteins were measured by RT-qPCR and Western blotting;lnc-MGC and miR-495-3p were detected by fluorescent in situ hybridization;CCK-8 and TUNEL assays were used to detect cell viability and apoptosis;enzyme-linked immunosorbent assay was used to detect inflammatory factors;dual-luciferase gene assays were used to verify the targeting relationship;and the retina was observed by HE staining.RESULTS LEF1 and lnc-MGC have binding sites,and lnc-MGC can regulate the miR-495-3p/GRP78 molecular axis.In high glucose-treated cells,inflammation was aggravated,the intracellular reactive oxygen species concentration was increased,cell viability was reduced,apoptosis was increased,the ER response was intensified,and ferroptosis was increased.As an ER molecular chaperone,GRP78 regulates the ER and ferroptosis under the targeting of miR-495-3p,whereas inhibiting LEF1 can further downregulate the expression of lnc-MGC,increase the level of miR-495-3p,and sequentially regulate the level of GRP78 to alleviate the occurrence and development of DR.Animal experiments indicated that the knockdown of LEF1 can affect the lnc-MGC/miR-495-3p/GRP78 signaling axis to restrain the progression of DR.CONCLUSION LEF1 knockdown can regulate the miR-495-3p/GRP78 molecular axis through lnc-MGC,which affects ER stress and restrains the progression of DR and ferroptosis in retinal pigment epithelial cells.
基金Supported by the Council for Science,Technology,and Innovation(CSTI)Cross-Ministerial Strategic Innovation Promotion Program(SIP)“Innovative AI Hospital System”(National Institute of Biomedical Innovation,Health and Nutrition),No.SIPAIH18C03the Japan Society for the Promotion of Science(JSPS)KAKENHI,No.JP19K09179 and No.JP23K08158.
文摘BACKGROUND Some patients with resectable or borderline resectable pancreatic ductal adenocarcinoma(PDAC)may have distant metastases,undetected on preoperative imaging or early recurrence,within 6 months after surgery.Occult metastases(OMs)must be accurately predicted to optimize multidisciplinary treatment.AIM To investigate the efficacy of circulating tumor DNA(ctDNA)in predicting OM.METHODS Two Japanese institutions prospectively collected preoperative plasma samples from PDAC patients between July 2019 and September 2021 and evaluated ctDNA using a targeted next-generation sequencing panel covering 52 cancer-related genes.RESULTS Among 135 PDAC patients,38 had OM and 35 were positive for ctDNA.The ctDNA positivity rate was significantly higher in patients with OM than in patients without OM.ctDNA-positive patients had significantly shorter median recurrence-free survival than ctDNA-negative patients.Logistic multivariate regression revealed ctDNA positivity as an independent predictor of OM.CONCLUSION Preoperative ctDNA in resectable PDAC is an independent predictor of OM and indicates poor prognosis following pancreatectomy and may be a useful biomarker in determining multidisciplinary patient care.
基金supported by the National Key R&D Program of China(No.2022YFA1303600 and No.2023YFC2306800)the National Natural Science Foundation of China(No.82372235 and No.82272315)the Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.
基金supported by grants from the National Natural Science Foundation of China(81672422 and 81600506)Natural Science Foundation of Zhejiang Province(LY15H160033)+4 种基金Zhejiang Province Health Department Program(2014KYB081 and 2017KY322)Open Project in State Key Laboratory for Diagnosis and Treatment of Infectious Disease(2015KF03)Academician JieShou Li Intestinal Mucosal Barrier Fund(201208)Medical S&T Project of Zhejiang Province(201479797)National S&T Major Project of China(2018ZX10301201)
文摘Background: Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and HCC development through the gut-liver axis. Data sources: Recently there have been several innovative studies investigating gut microbial dysbiosismediated enhancement of HCC through the gut-liver axis. Literatures from January 1998 to January 2018 were searched in the Pub Med database using the keywords "gut microbiota" and "hepatocellular carcinoma" or "liver cancer", and the results of experimental and clinical studies were analyzed. Results: Gut microbial dysbiosis accompanies the progression of alcoholic liver disease, non-alcoholic fatty liver disease and liver cirrhosis, and promotes HCC progression in an experimental mouse model. The immune system and key factors such as Toll-like receptor 4 are involved in the process. There is evidence for gut microbial dysbiosis in hepatitis virus-related HCC patients. Conclusions: Gut microbial dysbiosis is closely associated with hepatic inflammation disease and HCC through the gut-liver axis. With the enhanced understanding of the interactions between gut microbiota and liver through the gut-liver axis, new treatment strategies for HCC are being developed.
基金supported by National Natural Science Foundation of China(81473091,81673290 and U1603123)
文摘OBJECTIVE To discover a small-molecule bromodomain-containing protein 4(BRD4)inhibitor that induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast cancer and exploreits potential mechanisms.METHODS BRD4 interactors were analyzed by PPI network prediction and The Cancer Genome Atlas(TCGA)analysis.The interaction between BRD4 and AMPK was confirmed by co-immunoprecipitation assay.Novel BRD4 inhibitors were designed and synthesized based upon pharmacophore analysis of BRD4(1),then screened by antiproliferative activity and Alpha Screen of BRD4(1).The selectivity of the best candidate compound 8f was validated by co-crystallization,FRET assay and co-immuno precipitation assay.The mechanisms of 8f were investigated by fluorescence microscopy,electron microscopy,Western blotting,immunocytochemistry,si RNA and GFP-m RFP-LC3 plasmid transfections,as well as immunohistochemistry and immunofluorescence.Potential mechanisms were discovered by i TRAQ-based proteomics analysis and the therapeutic effect of 8f was assessed by xenograft breast cancer mouse and zebrafish models.RESULTS We identified that BRD4 interacted with AMPK,which was remarkably downregulated in breast cancer.We next designed and synthesized 49 candidate compounds,and eventually discovered a selective small-molecule inhibitor of BRD4(8f).Subsequently,8f was discovered to induce autophagyassociated cell death(ACD)by BRD4-AMPK interaction,and thus activating AMPK-m TOR-ULK1-modulated autophagic pathway in breast cancer cells.Interestingly,the i TRAQ-based proteomics analyses revealed that 8f induced ACD pathways,involved in HMGB1,VDAC1/2 and e EF2.Moreover,8f displayed a therapeutic potential on both xenograft breast cancer mouse and zebrafish models.CONCLUSION We discovered a novel small-molecule inhibitor of BRD4 that induces BRD4-AMPK-modulated ACD in breast cancer,which may provide a candidate drug for future cancer therapy.
基金National Key Research and Development Program of China,No.2018YFC2000500Research Project of Jinan Microecological Biomedicine Shandong Laboratory,No.JNL-2022001ANational Natural Science Foundation of China,No.U2004121,No.82070643 and No.U1904164
文摘Hepatitis B virus(HBV)has posed a threat to public health,mainly resulting in liver damage.With long-term accumulation of extracellular matrix,patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma.The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality.With deeper understanding of the bidirectional interaction between the liver and the gut(gut-liver axis),there is a growing consensus that the human health closely relates to the gut microbiota.Supported by animal and human studies,the gut microbiota alters as the HBV-related liver fibrosis initials and progresses,characterized as the decrease of the ratio between“good”and“potentially pathogenic”microbes.When the primary disease is controlled via antiviral treatment,the gut microbiota dysfunction tends to be improved.Conversely,the recovery of gut microbiota can promote the regression of liver fibrosis.Therapeutic strategies targeted on gut microbiota(rifaximin,probiotics,engineered probiotics and fecal microbiota transplantation)have been applied to animal models and patients,obtaining satisfactory results.
基金supported by grants from the National Natural Science Foundation of China(U2004121,82070643,and U1904164)。
文摘Background:Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related death worldwide.Due to the high prevalence of hepatitis B virus(HBV)infection in China,the incidence of HCC in China is high,and liver cirrhosis caused by chronic hepatitis also brings great challenges to treatment.This paper reviewed the latest research progress on minimally invasive treatments for HCC,including percutaneous thermal ablation and new nonthermal ablation techniques,and introduced the principles,advantages,and clinical applications of various therapeutic methods in detail.Data sources:The data of treatments for HCC were systematically collected from the Pub Med,Science Direct,American Chemical Society and Web of Science databases published in English,using“minimally invasive”and“hepatocellular carcinoma”or“liver cancer”as the keywords.Results:Percutaneous thermal ablation is still a first-line strategy for the minimally invasive treatment of HCC.The effect of microwave ablation(MWA)on downgrading treatment before liver transplantation is better than that of radiofrequency ablation(RFA),while RFA is more widely used in the clinical practice.High-intensity focused ultrasound(HIFU)is mainly used for the palliative treatment of advanced liver cancer.Electrochemotherapy(ECT)delivers chemotherapeutic drugs to the target cells while reducing the blood supply around HCC.Irreversible electroporation(IRE)uses a microsecond-pulsed electric field that induces apoptosis and necrosis and triggers a systemic immune response.The nanosecond pulsed electric field(ns PEF)has achieved a good response in the ablation of mice with HCC,but it has not been reported in China for the treatment of human HCC.Conclusions:A variety of minimally invasive treatments provide a sufficient survival advantage for HCC patients.Nonthermal ablation will lead to a new wave with its unique advantage of antitumor recurrence and metastasis.
基金supported by grants from the National S&T Major Project of China(2018ZX10301201)the National Natu-ral Science Foundation of China(81702757,81702346,81600506,81702927,81500127)+1 种基金Youth Innovation Fund of the First Affiliated Hospital of Zhengzhou University(YNQN2017167,YNQN2017031 and YNQN2017032)the Joint Research Fund of the First Affiliated Hospital of Zhengzhou University and Dalian Institute of Chemical Physics Chinese Academy of Sciences
文摘Background:microRNA-139(miR-139)is dysregulated in various types of tumors and plays a key role in carcinogenesis.miR-139 may be used as a diagnostic and prognostic biomarker of cancers.However,the data from the literature are not consistent.The present study aimed to verify the prognostic and diagnostic values of miR-139 in solid tumors.Data sources:PubMed,Web of Science and Embase databases were searched and publications from January 2011 to August 2017 were included.We used Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)database to further validate this meta-analysis.Results:Eight individual studies from seven articles were included.Pooled analyses showed that low miR-139 expression was related to worse overall survival(OS)[hazard ratio(HR)=2.27;95%confidence intervals(CI):1.74–2.95;P<0.001]in solid tumors,including hepatocellular carcinoma(HCC)and glioblastoma multiforme(GBM),consisting with the results of TCGA.However,our results of CRC showed that low miR-139 expression was associated with poor OS which was contradictory with the results in TCGA database and need larger samples to validate the phenomenon;whereas for CRC patients,high miR-139 expression predicted poor RFS,which was in good accordance with TCGA results.The results of 27 microarrays from GEO database showed that miR-139 expression levels were lower in tumor tissues compared to adjacent non-tumor tissues or healthy tissues.Decreased miR-139 expression was also significantly correlated with poor differentiation grade(OR=3.57;95%CI:1.44–8.85;P=0.006).However,the combined data indicated that no associations between miR-139 expression and the following parameters such as age(pooled OR=1.50;95%CI:0.69–3.24;P=0.304),gender(pooled OR=0.92;95%CI:0.56–1.51;P=0.738),tumor size(pooled OR=1.51;95%CI:0.69–3.31;P=0.298),late tumor-node-metastasis stage(pooled OR=1.63;95%CI:0.99–2.68;P=0.057)and lymph-node-metastasis(pooled OR=0.66;95%CI:0.34–1.28;P=0.222).Conclusions:Low miR-139 expression was related to poor prognosis in HCC and GBM,which could be regarded as a potential prognostic biomarker.However,its precise functional role in CRC still need to be further investigated through larger samples and multicenter studies.
基金supported by grants from the National Key Research and Development Program of China(2018YFC2000501)National Natural Science Foundation of China(81600506)+1 种基金National S&T Major Project of China(2018ZX10301201-008)China Postdoctoral Science Foundation(2017M610463 and 2018M632814).
文摘Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.
基金supported by a grant from the National Natural Science Foundation of China(No.82072210)the Shanghai Municipal Science and Technology Commission,China(No.20ZR1445200)+1 种基金the Chinese Federation of Public Health Foundation(GWLM202001)the Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(No.GWV-10.1-XK25).
文摘The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.
基金supported by the Key National Research and Development Program (No. 2016YFD0200602)the National Basic Research Program (No. 2015CB150405)+1 种基金the National Natural Science Foundation (No. 31421092)the SINOGRAIN Project (No. CHN-2152, 14-0039) of China
文摘In-season diagnosis of crop nitrogen(N) status is crucial for precision N management. Critical N(N_c) dilution curve and N nutrition index(NNI) have been proposed as effective methods to diagnose N status of different crops. The N_c dilution curves have been developed for indica rice in the tropical and temperate zones and japonica rice in the subtropical-temperate zone, but they have not been evaluated for short-season japonica rice in Northeast China. The objectives of this study were to evaluate the previously developed N_c dilution curves for rice in Northeast China and to develop a more suitable N_c dilution curve in this region. A total of17 N rate experiments were conducted in Sanjiang Plain, Heilongjiang Province in Northeast China from 2008 to 2013. The results indicated that none of the two previously developed N_c dilution curves was suitable to diagnose N status of the short-season japonica rice in Northeast China. A new N_c dilution curve was developed and can be described by the equation N_c = 27.7 W^(-0.34) if W ≥ 1 Mg dry matter(DM) ha^(-1) or N_c = 27.7 g kg^(-1) DM if W < 1 Mg DM ha^(-1), where W is the aboveground biomass. This new curve was lower than the previous curves. It was validated using a separate dataset, and it could discriminate non-N-limiting and N-limiting nutritional conditions. Additional studies are needed to further evaluate it for diagnosing N status of different rice cultivars in Northeast China and develop efficient non-destructive methods to estimate NNI for practical applications.
