ABSTRACT
Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.
Subject(s)
Adipocytes/metabolism , Energy Metabolism , Interleukin-27/metabolism , Thermogenesis , Animals , Bariatric Surgery , Disease Models, Animal , Female , Humans , Insulin Resistance , Interleukin-27/blood , Interleukin-27/therapeutic use , Male , Mice , Obesity/blood , Obesity/drug therapy , Obesity/metabolism , Obesity/prevention & control , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Receptors, Interleukin/metabolism , Signal Transduction , Uncoupling Protein 1/biosynthesis , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
SignificanceUnderstanding autophagy regulation is instrumental in developing therapeutic interventions for autophagy-associated disease. Here, we identified SNAI2 as a regulator of autophagy from a genome-wide screen in HeLa cells. Upon energy stress, SNAI2 is transcriptionally activated by FOXO3 and interacts with FOXO3 to form a feed-forward regulatory loop to reinforce the expression of autophagy genes. Of note, SNAI2-increased FOXO3-DNA binding abrogates CRM1-dependent FOXO3 nuclear export, illuminating a pivotal role of DNA in the nuclear retention of nucleocytoplasmic shuttling proteins. Moreover, a dFoxO-Snail feed-forward loop regulates both autophagy and cell size in Drosophila, suggesting this evolutionarily conserved regulatory loop is engaged in more physiological activities.
Subject(s)
Autophagy , Cell Nucleus , Forkhead Box Protein O3 , Snail Family Transcription Factors , Active Transport, Cell Nucleus , Animals , Autophagy/genetics , Cell Nucleus/genetics , Cell Nucleus/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Forkhead Box Protein O3/genetics , Forkhead Box Protein O3/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , HeLa Cells , Humans , Snail Family Transcription Factors/genetics , Snail Family Transcription Factors/metabolismABSTRACT
Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted.
Subject(s)
Ferroptosis , Nanomedicine , Neoplasms , Ferroptosis/drug effects , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Nanomedicine/methods , Animals , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic useABSTRACT
A unique feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of interleukin 10 (IL-10). This was thought to be a negative feedback mechanism to suppress inflammation. However, several lines of clinical evidence suggest that dramatic early proinflammatory IL-10 elevation may play a pathological role in COVID-19 severity.
Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Interleukin-10/immunology , SARS-CoV-2/immunology , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/metabolism , Epidemics , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/metabolism , Lymphocytes/immunology , Lymphocytes/metabolism , Models, Immunological , SARS-CoV-2/physiology , Severity of Illness IndexABSTRACT
Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes of cancer-related deaths worldwide, approximately 70% of patients with HCC exhibit advanced disease at diagnosis, limiting the potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib for first-line targeted therapy, has become a key treatment. Unfortunately, despite some progress, the prognosis for advanced HCC remains poor because of drug resistance development. However, the molecular mechanisms underlying lenvatinib resistance and ways to relief drug resistance in HCC are largely unknown and lack of systematic summary; thus, this review not only aims to explore factors contributing to lenvatinib resistance in HCC, but more importantly, summary potential methods to conquer or mitigate the resistance. The results suggest that abnormal activation of pathways, drug transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, and other mechanisms are involved in the development of lenvatinib resistance in HCC and subsequent HCC progression. To improve the therapeutic outcomes of lenvatinib, inhibiting acquired resistance, combined therapies, and nano-delivery carriers may be possible approaches.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Drug Resistance, Neoplasm , Liver Neoplasms , Phenylurea Compounds , Quinolines , Carcinoma, Hepatocellular/drug therapy , Humans , Quinolines/therapeutic use , Quinolines/pharmacology , Phenylurea Compounds/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Tumor Microenvironment/drug effects , Epithelial-Mesenchymal Transition/drug effects , Neoplastic Stem Cells/drug effects , Protein Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND AND AIMS: The transjugular intrahepatic portosystemic shunt has controversial survival benefits; thus, patient screening should be performed preoperatively. In this study, we aimed to develop a model to predict post-transjugular intrahepatic portosystemic shunt mortality to aid clinical decision making. METHODS: A total of 811 patients undergoing transjugular intrahepatic portosystemic shunt from five hospitals were divided into the training and external validation data sets. A modified prediction model of post-transjugular intrahepatic portosystemic shunt mortality (ModelMT ) was built after performing logistic regression. To verify the improved performance of ModelMT , we compared it with seven previous models, both in discrimination and calibration. Furthermore, patients were stratified into low-, medium-, high- and extremely high-risk subgroups. RESULTS: ModelMT demonstrated a satisfying predictive efficiency in both discrimination and calibration, with an area under the curve of .875 in the training set and .852 in the validation set. Compared to previous models (ALBI, BILI-PLT, MELD-Na, MOTS, FIPS, MELD, CLIF-C AD), ModelMT showed superior performance in discrimination by statistical difference in the Delong test, net reclassification improvement and integrated discrimination improvement (all p < .050). Similar results were observed in calibration. Low-, medium-, high- and extremely high-risk groups were defined by scores of ≤160, 160-180, 180-200 and >200, respectively. To facilitate future clinical application, we also built an applet for ModelMT . CONCLUSIONS: We successfully developed a predictive model with improved performance to assist in decision making for transjugular intrahepatic portosystemic shunt according to survival benefits.
Subject(s)
Portasystemic Shunt, Transjugular Intrahepatic , Humans , Retrospective Studies , Liver Cirrhosis/complications , Liver Cirrhosis/surgery , Treatment OutcomeABSTRACT
Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 µM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.
Subject(s)
Polyenes , Polyenes/chemistry , Polyenes/pharmacology , Molecular Structure , Talaromyces/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Respiratory Syncytial Viruses/drug effects , HumansABSTRACT
Hepatocellular carcinoma (HCC) is among the most common malignancies worldwide and is characterized by high rates of morbidity and mortality, posing a serious threat to human health. Interventional embolization therapy is the main treatment against middle- and late-stage liver cancer, but its efficacy is limited by the performance of embolism, hence the new embolic materials have provided hope to the inoperable patients. Especially, hydrogel materials with high embolization strength, appropriate viscosity, reliable security and multifunctionality are widely used as embolic materials, and can improve the efficacy of interventional therapy. In this review, we have described the status of research on hydrogels and challenges in the field of HCC therapy. First, various preparation methods of hydrogels through different cross-linking methods are introduced, then the functions of hydrogels related to HCC are summarized, including different HCC therapies, various imaging techniques, in vitro 3D models, and the shortcomings and prospects of the proposed applications are discussed in relation to HCC. We hope that this review is informative for readers interested in multifunctional hydrogels and will help researchers develop more novel embolic materials for interventional therapy of HCC.
Subject(s)
Carcinoma, Hepatocellular , Embolization, Therapeutic , Hydrogels , Liver Neoplasms , Hydrogels/chemistry , Liver Neoplasms/therapy , Carcinoma, Hepatocellular/therapy , Humans , Animals , Embolization, Therapeutic/methodsABSTRACT
AIM: This study aimed to explore whether the addition of sarcopenia and visceral adiposity could improve the accuracy of model predicting progression-free survival (PFS) in hepatocellular carcinoma (HCC). METHODS: In total, 394 patients with HCC from five hospitals were divided into the training and external validation datasets. Patients were initially treated by liver resection or transarterial chemoembolization. We evaluated adipose and skeletal muscle using preoperative computed tomography imaging and then constructed three predictive models, including metabolic (ModelMA), clinical-imaging (ModelCI), and combined (ModelMA-CI) models. Their discrimination, calibration, and decision curves were compared, to identify the best model. Nomogram and subgroup analysis was performed for the best model. RESULTS: ModelMA-CI containing sarcopenia and visceral adiposity had good discrimination and calibrations (integrate area under the curve for PFS was 0.708 in the training dataset and 0.706 in the validation dataset). ModelMA-CI had better accuracy than ModelCI and ModelMA. The performance of ModelMA-CI was not affected by treatments or disease stages. The high-risk subgroup (scored > 198) had a significantly shorter PFS (p < 0.001) and poorer OS (p < 0.001). CONCLUSIONS: The addition of sarcopenia and visceral adiposity improved accuracy in predicting PFS in HCC, which may provide additional insights in prognosis for HCC in subsequent studies.
Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Sarcopenia , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/pathology , Sarcopenia/diagnostic imaging , Sarcopenia/etiology , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Liver Neoplasms/pathology , Adiposity , Chemoembolization, Therapeutic/methods , Prognosis , Nomograms , Retrospective StudiesABSTRACT
The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In Drosophila, oncogenic RasV12 cooperates with loss-of-cell polarity to promote Hippo pathway-dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the Drosophila RasV12/lgl-/- in vivo tumor model and identified Rox8, a RNA-binding protein (RBP), as a positive regulator of the Hippo pathway. We found that Rox8 overexpression suppresses whereas Rox8 depletion potentiates Hippo-dependent tissue overgrowth, accompanied by altered Yki protein level and target gene expression. Mechanistically, Rox8 directly binds to a target site located in the yki 3' UTR, recruits and stabilizes the targeting of miR-8-loaded RISC, which accelerates the decay of yki messenger RNA (mRNA). Moreover, TIAR, the human ortholog of Rox8, is able to promote the degradation of yki mRNA when introduced into Drosophila and destabilizes YAP mRNA in human cells. Thus, our study provides in vivo evidence that the Hippo pathway is posttranscriptionally regulated by the collaborative action of RBP and microRNA (miRNA), which may provide an approach for modulating Hippo pathway-mediated tumorigenesis.
Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/genetics , MicroRNAs/genetics , Nuclear Proteins/genetics , RNA, Messenger , RNA-Binding Proteins/genetics , Trans-Activators/genetics , 3' Untranslated Regions , Animals , Cell Proliferation , Fluorescent Antibody Technique , Gene Expression Regulation , Hippo Signaling Pathway , Humans , Models, Biological , Organ Specificity , Protein Serine-Threonine Kinases/metabolism , RNA Interference , RNA Stability , Signal Transduction , YAP-Signaling ProteinsABSTRACT
It is difficult to accurately understand the angioarchitecture of cerebral arteriovenous malformations (CAVMs) before surgery using existing imaging methods. This study aimed to evaluate the ability of the stereoscopic virtual reality display system (SVRDS) to display the angioarchitecture of CAVMs by comparing its accuracy with that of the conventional computed tomography workstation (CCTW). Nineteen patients with CAVM confirmed on digital subtraction angiography (DSA) or during surgery were studied. Computed tomography angiography images in the SVRDS and CCTW were retrospectively analyzed by two experienced neuroradiologists using a double-blind method. Angioarchitectural parameters, such as the location and size of the nidus, type and number of the arterial feeders and draining veins, and draining pattern of the vessels, were recorded and compared. The diameter of the nidus ranged from 1.1 to 9 cm. Both CCTW and SVRDS correctly diagnosed the location of the nidus in 19 patients with CAVM. Among the 19 patients, 35 arterial feeders and 25 draining veins were confirmed on DSA and during surgery. With the DSA and intraoperative results as the gold standard bases, the CCTW misjudged one arterial feeder and one draining vein and missed three arterial feeders and two draining veins; meanwhile, the SVRDS missed only two arterial feeders. SVRDS had some advantages in displaying nidus, arterial branches, and draining veins of the CAVM compared with CCTW, as well as SVRDS could more intuitively display the overall angio-architectural spatial picture of CAVM.
Subject(s)
Intracranial Arteriovenous Malformations , Virtual Reality , Humans , Retrospective Studies , Intracranial Arteriovenous Malformations/diagnostic imaging , Intracranial Arteriovenous Malformations/surgery , Cerebral Angiography , Tomography, X-Ray Computed/methods , Angiography, Digital SubtractionABSTRACT
The accuracy of computed tomography angiography (CTA) image interpretation depends on the radiologist. This study aims to develop a new method for automatically detecting intracranial aneurysms from CTA images using deep learning, based on a convolutional neural network (CNN) implemented on the DeepMedic platform. Ninety CTA scans of patients with intracranial aneurysms are collected and divided into two datasets: training (80 subjects) and test (10 subjects) datasets. Subsequently, a deep learning architecture with a three-dimensional (3D) CNN model is implemented on the DeepMedic platform for the automatic segmentation and detection of intracranial aneurysms from the CTA images. The samples in the training dataset are used to train the CNN model, and those in the test dataset are used to assess the performance of the established system. Sensitivity, positive predictive value (PPV), and false positives are evaluated. The overall sensitivity and PPV of this system for detecting intracranial aneurysms from CTA images are 92.3% and 100%, respectively, and the segmentation sensitivity is 92.3%. The performance of the system in the detection of intracranial aneurysms is closely related to their size. The detection sensitivity for small intracranial aneurysms (≤ 3 mm) is 66.7%, whereas the sensitivity of detection for large (> 10 mm) and medium-sized (3-10 mm) intracranial aneurysms is 100%. The deep learning architecture with a 3D CNN model on the DeepMedic platform can reliably segment and detect intracranial aneurysms from CTA images with high sensitivity.
Subject(s)
Deep Learning , Intracranial Aneurysm , Humans , Computed Tomography Angiography , Tomography, X-Ray Computed/methods , Angiography, Digital Subtraction/methods , Cerebral Angiography/methods , Sensitivity and SpecificityABSTRACT
OBJECTIVE: Patients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC). DESIGN: A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies. RESULTS: We demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties. CONCLUSIONS: Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Mice , Carcinoma, Hepatocellular/metabolism , B7-H1 Antigen/metabolism , Liver Neoplasms/metabolism , Mice, Inbred C57BL , Mice, Inbred Strains , MacrophagesABSTRACT
BACKGROUND: Cervical cancer is the most fatal gynecological carcinoma in the world. It is urgent to explore novel prognostic biomarkers and intervention targets for cervical cancer. METHODS: Through integrated quantitative proteomic strategy, we investigated the protein expression profiles of cervical cancer; 28 fresh frozen tissue samples (11 adenocarcinoma (AC), 12 squamous cell carcinoma (SCC) and 5 normal cervixes (HC)) were included in discover cohort; 45 fresh frozen tissue samples (19 AC, 18 SCC and 8 HC) were included in verification cohort; 140 paraffin-embedded tissues samples of cervical cancer (85 AC and 55 SCC) were used for immunohistochemical evaluation (IHC) of coatomer protein subunit alpha (COPA) as a prognostic biomarker for cervical cancer; how deficiency of COPA affects cell viability and tumorigenic ability of cervical cancer cells (SiHa cells and HeLa cells) were evaluated by cell counting kit-8 and clone formation in vitro. RESULTS: We identified COPA is a potential prognostic biomarker for cervical cancer in quantitative proteomics analysis. By retrospective IHC analysis, we additionally verified the proteomics results and demonstrated moderate or strong IHC staining for COPA is an unfavourable independent prognostic factor for cervical cancer. We also identified COPA is a potential pharmacological intervention target of cervical cancer by a series of in vitro experiments. CONCLUSION: This study is the first to demonstrate that COPA may contribute to progression of cervical cancer. It can serve as a potential prognostic biomarker and promising intervention target for cervical cancer.
Subject(s)
Coatomer Protein , Uterine Cervical Neoplasms , Biomarkers , Biomarkers, Tumor/metabolism , Female , HeLa Cells , Humans , Prognosis , Proteomics , Retrospective Studies , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/metabolismABSTRACT
OBJECTIVES: Portal vein tumour thrombus (PVTT)-related symptomatic portal hypertension (SPH) leads to a poor prognosis in hepatocellular carcinoma (HCC) patients. A transjugular intrahepatic portosystemic shunt (TIPS) can effectively relieve SPH but its effect remains unclear in PVTT-related SPH. This study aimed to evaluate the clinical value of the TIPS procedure combined with sequential systemic therapy in advanced HCC patients with PVTT-related SPH. METHODS: After 1:1 propensity score matching (PSM), this retrospective study analysed 42 patients who underwent TIPS placement plus sequential systemic therapy (group A) and 42 patients who received only symptomatic and supportive treatment (group B). The evaluated outcomes were overall survival (OS) and SPH control rate. Cox proportional hazards regression analysis was used to compare OS in the two groups. RESULTS: In group A, the technical success rate of the TIPS procedure was 95.2%, and no severe complications occurred. The rebleeding rates in group A and group B were 5.0% and 73.7%, respectively (p < 0.001), and the ascites control rates were 92.0% and 28.0%, respectively (p < 0.001). The median OS of group A was significantly better than that of group B (9.6 [95% CI: 7.1, 12.0] vs. 4.9 [95% CI: 3.9, 5.8], months, p < 0.001). Multivariable analysis showed that TIPS plus sequential systemic therapy (hazard ratio [HR] = 5.799; 95% CI: 3.177, 10.585; p < 0.001) was an independent prognostic factor related to OS. Additionally, PVTT degree (I+II) (p = 0.008), AFP ≤ 400 ng/ml (p = 0.003), and Child-Pugh class A (p = 0.046) were significant predictors of OS. CONCLUSION: TIPS plus sequential systemic therapy is safe and feasible for treating advanced HCC with tumour thrombus-related SPH. KEY POINTS: ⢠Portal vein tumour thrombus (PVTT) is common in advanced hepatocellular carcinoma (HCC) and transforms compensated portal hypertension into symptomatic portal hypertension (SPH). ⢠HCC patients with PVTT-related SPH have a very poor prognosis, and there are no effective treatments recommended by the guidelines. ⢠Therefore, a treatment strategy that utilises a transjugular intrahepatic portosystemic shunt (TIPS) to manage SPH combined with sequential systemic therapy in advanced HCC patients is explored in this study for its feasibility and clinical value. This research can fill the gap in current research data to provide clinically meaningful treatment options.
Subject(s)
Carcinoma, Hepatocellular , Hypertension, Portal , Liver Neoplasms , Thrombosis , Carcinoma, Hepatocellular/pathology , Humans , Hypertension, Portal/etiology , Liver Neoplasms/pathology , Portal Vein/pathology , Retrospective Studies , Thrombosis/complications , Thrombosis/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Main challenges for COVID-19 include the lack of a rapid diagnostic test, a suitable tool to monitor and predict a patient's clinical course and an efficient way for data sharing among multicenters. We thus developed a novel artificial intelligence system based on deep learning (DL) and federated learning (FL) for the diagnosis, monitoring, and prediction of a patient's clinical course. METHODS: CT imaging derived from 6 different multicenter cohorts were used for stepwise diagnostic algorithm to diagnose COVID-19, with or without clinical data. Patients with more than 3 consecutive CT images were trained for the monitoring algorithm. FL has been applied for decentralized refinement of independently built DL models. RESULTS: A total of 1,552,988 CT slices from 4804 patients were used. The model can diagnose COVID-19 based on CT alone with the AUC being 0.98 (95% CI 0.97-0.99), and outperforms the radiologist's assessment. We have also successfully tested the incorporation of the DL diagnostic model with the FL framework. Its auto-segmentation analyses co-related well with those by radiologists and achieved a high Dice's coefficient of 0.77. It can produce a predictive curve of a patient's clinical course if serial CT assessments are available. INTERPRETATION: The system has high consistency in diagnosing COVID-19 based on CT, with or without clinical data. Alternatively, it can be implemented on a FL platform, which would potentially encourage the data sharing in the future. It also can produce an objective predictive curve of a patient's clinical course for visualization. KEY POINTS: ⢠CoviDet could diagnose COVID-19 based on chest CT with high consistency; this outperformed the radiologist's assessment. Its auto-segmentation analyses co-related well with those by radiologists and could potentially monitor and predict a patient's clinical course if serial CT assessments are available. It can be integrated into the federated learning framework. ⢠CoviDet can be used as an adjunct to aid clinicians with the CT diagnosis of COVID-19 and can potentially be used for disease monitoring; federated learning can potentially open opportunities for global collaboration.
Subject(s)
Artificial Intelligence , COVID-19 , Algorithms , Humans , Radiologists , Tomography, X-Ray Computed/methodsABSTRACT
Drugs are frequently used for only chemotherapy that ignores their photophysical properties that potentially endow them with other therapeutic potency. Additionally, current photothermal-chemotherapy replies on the codelivery of drugs and photothermal agents, but their spatiotemporal delivery and precise release is unsatisfactory. Herein, label-free doxorubicin (DOX) polyprodrug nanoparticles (DPNs) are formulated from disulfide bonds-tethered DOX polyprodrug amphiphiles (PDMA-b-PDOXM). Benefiting from boosted nonradiative decay of high-density DOX, significant fluorescence quenching and photothermal effects are observed for DPNs without common photothermal agents. Upon cellular uptake and laser irradiation, the heat can promote lysosomal escape of DPNs into reductive cytosol, whereupon free DOX is released to activate chemotherapy and fluorescence, achieving rational cascade photothermal-chemotherapy. The current label-free polyprodrug strategy can make full use of drugs; it provides an alternative insight to extend the therapeutic domain of drugs.
Subject(s)
Hyperthermia, Induced , Nanoparticles , Neoplasms , Cell Line, Tumor , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Drug Liberation , Humans , Neoplasms/drug therapy , Neoplasms/pathology , PhototherapyABSTRACT
BACKGROUND: The pelvic autonomic nerves control and regulate anorectal and urogenital function. The dysfunction of pelvic autonomic nerves lead to disorders of anorectum, bladder and male sex organs. Thus the intraoperative identification of pelvic autonomic nerves could be crucial in complications prevention and diseases treatment. Our clinical trial aims at estimating the effectiveness and validity of intraoperative indocyanine green fluorescence imaging in pelvic autonomic nerves identification. METHODS: Intraoperative fluorescence imaging using indocyanine green was performed in ten patients and the feasibility was determined. From February 2019 to June 2019, the seven patients undergoing laparoscopic colorectal resection was administrated 4.5 mg/Kg indocyanine green 24 h before surgery. The near-infrared fluorescence imaging was conducted during surgery. A novel white light and near-infrared dual-channel laparoscopic equipment was applied. For each patient, signal-background ratio values for pelvic autonomic nerves were recorded and analyzed. RESULTS: We confirmed the dose and timing of indocyanine green administration was 4.5 mg/Kg and 24 h before surgery. Using the dual laparoscopic equipment, we could observe the splanchnic plexus, inferior mesenteric artery plexus, and sacral plexus successfully with a high signal background ratio value of 3.18 (standard deviation: 0.48). CONCLUSION: This pilot trial shows feasibility of intraoperative indocyanine green fluorescence imaging in pelvic autonomic nerves observation. It demonstrates that nerves can be visualized using alternative imaging techniques but it is not ready yet for prime time. This technique might aid observation with white light alone. REGISTRATION NUMBER: ChiCTR1900025336.
Subject(s)
Indocyanine Green , Laparoscopy , Autonomic Pathways , Female , Humans , Laparoscopy/methods , Male , Optical Imaging/methods , Pelvis/diagnostic imaging , Pelvis/innervation , Pilot ProjectsABSTRACT
Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.
Subject(s)
Extracellular Matrix/metabolism , Immunotherapy , Membrane Proteins , Nanoparticles , Phototherapy , Animals , Female , Membrane Proteins/agonists , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Nanoparticles/metabolism , Photochemical ProcessesABSTRACT
BACKGROUND: As reported, preclinical animal models differ greatly from the human body. The evaluation model may be the colossal obstacle for scientific research and anticancer drug development. Therefore, it is essential to propose efficient evaluation systems similar to clinical practice for cancer research. MAIN BODY: While it has emerged for decades, the development of patient-derived xenografts, patient-derived organoid and patient-derived cell used to be limited. As the requirements for anticancer drug evaluation increases, patient-derived models developed rapidly recently, which is widely applied in basic research, drug development, and clinical application and achieved remarkable progress. However, there still lack systematic comparison and summarize reports for patient-derived models. In the current review, the development, applications, strengths, and challenges of patient-derived models in cancer research were characterized. CONCLUSION: Patient-derived models are an indispensable approach for cancer research and human health.