ABSTRACT
While metaverse is widely discussed, comprehension of its intricacies remains limited to a select few. Conceptually akin to a three-dimensional embodiment of the Internet, the metaverse facilitates simultaneous existence in both physical and virtual domains. Fundamentally, it embodies a visually immersive virtual environment, striving for authenticity, where individuals engage in real-world activities such as commerce, gaming, social interaction, and leisure pursuits. The global pandemic has accelerated digital innovations across diverse sectors. Beyond strides in telehealth, payment systems, remote monitoring, and secure data exchange, substantial advancements have been achieved in artificial intelligence (AI), virtual reality (VR), augmented reality (AR), and blockchain technologies. Nevertheless, the metaverse, in its nascent stage, continues to evolve, harboring significant potential for revolutionizing healthcare. Through integration with the Internet of Medical Devices, quantum computing, and robotics, the metaverse stands poised to redefine healthcare systems, offering enhancements in surgical precision and therapeutic modalities, thus promising profound transformations within the industry.
Subject(s)
Virtual Reality , Humans , Delivery of Health Care , Artificial Intelligence , Telemedicine , Augmented Reality , Blockchain , COVID-19ABSTRACT
The complex global context, including globalization, rapid urbanization, and climate change, poses significant challenges to urban stability and development. Balancing urban land use efficiency and resilience is crucial for sustainable progress. Focusing on the vulnerable Yellow River Basin (YRB), this study examines the interplay between urban resilience and land use efficiency. Panel data from 2013 to 2020 for 54 cities in the YRB were used, it quantifies the Coupling Coordination Degree of Urban Resilience and Urban Land Use Efficiency (CCDUU), explores its spatiotemporal evolution and influencing factors. Key findings include: The CCDUU exhibits a sustained and discernible growth trend. Notably, CCDUU is higher in downstream areas in comparison to the middle reaches, reaching its lowest point in the upstream areas; however, the increase in CCDUU in the upstream areas surpasses that observed in other regions. Concurrently, regional disparities in CCDUU are diminishing. Despite the presence of a notable positive spatial correlation in CCDUU within the YRB, the strength of this spatial association is not sufficiently robust. Of paramount importance factor is the role of regional innovation, which significantly influences the enhancement of CCDUU. Following closely is the degree of openness, whereas the positive effects of government support and population density are concentrated predominantly in the upper YRB region. In contrast, urban-rural disparity exerts an adverse impact on CCDUU in most regions. Policy recommendations for enhancing CCDUU in YRB cities include strengthening government support and planning control, particularly in upstream regions, to achieve efficient resource utilization and environmental protection. Implementing population density management policies, encouraging rational movement, and promoting population migration to upstream areas can alleviate pressure in downstream cities. Enhancing openness, attracting foreign investment, and promoting innovation and industrial upgrading will drive economic structural upgrades and improve CCDUU.
ABSTRACT
Background: Colorectal cancer (CRC) has a high morbidity and mortality. Ferroptosis is a phenomenon in which metabolism and cell death are closely related. The role of ferroptosis-related genes in the progression of CRC is still not clear. Therefore, we screened and validated the ferroptosis-related genes which could determine the prevalence, risk and prognosis of patients with CRC. Methods: We firstly screened differentially expressed ferroptosis-related genes by The Cancer Genome Atlas (TCGA) database. Then, these genes were used to construct a risk-score model using the least absolute shrinkage and selection operator (LASSO) regression algorithm. The function and prognosis of the ferroptosis-related genes were confirmed using multi-omics analysis. The gene expression results were validated using publicly available databases and qPCR. We also used publicly available data and ferroptosis-related genes to construct a prognostic prediction nomogram. Results: A total of 24 differential expressed genes associated with ferroptosis were screened in this study. A three-gene risk score model was then established based on these 24 genes and GPX3, CDKN2A and SLC7A11 were selected. The significant prognostic value of this novel three-gene signature was also assessed. Furthermore, we conducted RT-qPCR analysis on cell lines and tissues, and validated the high expression of CDKN2A, GPX3 and low expression of SLC7A11 in CRC cells. The observed mRNA expression of GPX3, CDKN2A and SLC7A11 was consistent with the predicted outcomes. Besides, eight variables including selected ferroptosis related genes were included to establish the prognostic prediction nomogram for patients with CRC. The calibration plots showed favorable consistency between the prediction of the nomogram and actual observations. Also, the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. Conclusions: The present study constructed and validated a novel ferroptosis-related three-gene risk score signature and a prognostic prediction nomogram for patients with CRC. Also, we screened and validated the ferroptosis-related genes GPX3, CDKN2A, and SLC7A11 which could serve as novel biomarkers for patients with CRC.
Subject(s)
Amino Acid Transport System y+ , Biomarkers, Tumor , Colorectal Neoplasms , Ferroptosis , Gene Expression Regulation, Neoplastic , Nomograms , Humans , Ferroptosis/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Prognosis , Biomarkers, Tumor/genetics , Amino Acid Transport System y+/genetics , Male , Female , Cyclin-Dependent Kinase Inhibitor p16/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Middle Aged , Gene Expression Profiling , Risk Assessment/methods , Risk Assessment/statistics & numerical data , AgedABSTRACT
Introduction: Compared to other cancer immunotherapies, oncolytic viruses possess several advantages, including high killing efficiency, excellent targeting capabilities, minimal adverse reactions, and multiple pathways for tumor destruction. However, the efficacy of oncolytic viruses as a monotherapy often falls short of expectations. Consequently, combining oncolytic viruses with traditional treatments to achieve synergistic effects has emerged as a promising direction for the development of oncolytic virus therapies. Methods: This article provides a comprehensive review of the current progress in preclinical and clinical trials exploring the combination therapies involving oncolytic viruses. Results: Specifically, we discuss the combination of oncolytic viruses with immune checkpoint inhibitors, chemotherapy, targeted therapy, and cellular therapy. Discussion: The aim of this review is to offer valuable insights and references for the further advancement of these combination strategies in clinical applications. Further research is necessary to refine the design of combination therapies and explore novel strategies to maximize the therapeutic benefits offered by oncolytic viruses.
ABSTRACT
Nanoplastics (NPs) present in food and water poses a genuine risk of their accumulation in humans through the diet. Preferential contact between ingested NPs and the intestine as well as the liver has the potential to induce enteritis and hepatitis. However, there is still a lack of comprehensive understanding regarding the inter-organ crosstalk between the intestine and liver when exposed to NPs, as well as the underlying signaling pathways involved. In this study, we employed a 21-day mice exposure model to investigate the accumulation profile of PS-NPs and elucidate the mechanism of intestinal and hepatic inflammation induced by NPs. After exposure, notable fluorescent signals originating from PS-NPs were detected not only in the stomach and intestine but also in other organs such as liver, lung, kidney, brain, and testes. Histopathological analysis along with routine blood tests both revealed an acute inflammatory reaction in mice. Further mechanistic investigations demonstrated that PS-NPs activated inflammatory NF-κB/NLRP3 pathways and induced the expression of cytokines IL-1ß and IL-18 in the intestine, which recruited macrophages and neutrophils into the intestine. Concurrently, a significant decrease in the expression levels of intestinal tight junction proteins (Claudin-1, Occludin, and ZO-1) was observed, resulting in an increase in intestinal permeability and elevated endotoxin (LPS) levels. The high levels of LPS further activated TLR4/NF-κB/NLRP3/GSDMD pathways in the liver, inducing liver inflammation and hepatocyte pyroptosis. The impairment of liver function was positively correlated with intestinal inflammation and barrier disruption. These findings underscore that exposure to NPs can instigate enteritis and hepatitis while emphasizing the crucial role played by the indirect gut-liver axis in elucidating the potential mechanism underlying NP-induced liver pathogenesis.
Subject(s)
Liver , NF-kappa B , NLR Family, Pyrin Domain-Containing 3 Protein , Polystyrenes , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Mice , NF-kappa B/metabolism , Polystyrenes/toxicity , Liver/drug effects , Liver/metabolism , Inflammation/chemically induced , Signal Transduction/drug effects , Microplastics/toxicity , Intestines/drug effects , Male , Nanoparticles/toxicityABSTRACT
PURPOSE: To study the capability of diffusion-relaxation correlation spectroscopic imaging (DR-CSI) on subtype classification and grade differentiation for small renal cell carcinoma (RCC). Histogram analysis for apparent diffusion coefficient (ADC) was studied for comparison. MATERIALS AND METHODS: A total of 61 patients with small RCC (< 4 cm) were included in the retrospective study. MRI data were reviewed, including a multi-b (0-1500 s/mm2) multi-TE (51-200 ms) diffusion weighted imaging (DWI) sequence. Region of interest (ROI) was delineated manually on DWI to include solid tumor. For each patient, a D-T2 spectrum was fitted and segmented into 5 compartments, and the volume fractions VA, VB, VC, VD, VE were obtained. ADC mapping was calculated, and histogram parameters ADC 90th, 10th, median, standard deviation, skewness and kurtosis were obtained. All MRI metrices were compared between clear cell RCC (ccRCC) and non-ccRCC group, and between high-grade and low-grade group. Receiver operator curve analysis was used to assess the corresponding diagnostic performance. RESULTS: Significantly higher ADC 90th, ADC 10th and ADC median, and significantly lower DR-CSI VB was found for ccRCC compared to non-ccRCC. Significantly lower ADC 90th, ADC median and significantly higher VB was found for high-grade RCC compared to low-grade. For identifying ccRCC from non-ccRCC, VB showed the highest area under curve (AUC, 0.861) and specificity (0.882). For differentiating high- from low-grade, ADC 90th showed the highest AUC (0.726) and specificity (0.786), while VB also displayed a moderate AUC (0.715). CONCLUSION: DR-CSI may offer improved accuracy in subtype identification for small RCC, while do not show better performance for small RCC grading compared to ADC histogram.
Subject(s)
Carcinoma, Renal Cell , Diffusion Magnetic Resonance Imaging , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/diagnostic imaging , Male , Female , Diffusion Magnetic Resonance Imaging/methods , Retrospective Studies , Middle Aged , Aged , Adult , Neoplasm Grading , Aged, 80 and over , Sensitivity and SpecificityABSTRACT
BACKGROUND: The diagnosis of myasthenia gravis (MG) in children remains difficult. Circulating small extracellular vesicle (sEV)-derived miRNAs (sEV-miRNAs) have been recognized as biomarkers of various diseases and can be excreted by different cell types. These biomarker candidates also play a vital role in autoimmune diseases via intercellular communication. METHODS: In the present study, we used sEV isolation and purification methods to extract the plasma-derived sEV-miRNAs from children with MG and healthy controls. A small RNA sequencing analysis confirmed the miRNA expression features in plasma-derived sEVs from MG patients. The miRNA expression analysis in vitro was determined using microarray analysis. The enrichment and network analyses of altered sEV-miRNAs were performed using miRNA databases and Database for Annotation, Visualization, and Integrated Discovery website. Quantitative real-time polymerase chain reaction was performed for validation of sEV-miRNA. The diagnostic power of altered sEV-miRNAs was evaluated using receiver operating characteristic curve analyses. RESULTS: Twenty-four sEV-miRNAs with altered expression level were identified between groups by DESeq2 method. The miRNAs were extracted from the sEVs, which were isolated from human primary skeletal muscle cell culture treated with mAb198. The target genes and enriched pathways of sEV-miRNAs partially overlapped between cell supernatant and plasma samples. The significantly downregulated miR-143-3p was validated in quantitative real-time polymerase chain reaction analysis. CONCLUSIONS: For the first time, we report that plasma-derived sEV-miRNAs may act as novel circulating biomarkers and therapeutic targets in pediatric MG.
Subject(s)
Biomarkers , Extracellular Vesicles , MicroRNAs , Muscle, Skeletal , Myasthenia Gravis , Humans , Myasthenia Gravis/genetics , Myasthenia Gravis/blood , Myasthenia Gravis/diagnosis , Extracellular Vesicles/metabolism , Child , MicroRNAs/blood , Male , Female , Biomarkers/blood , Muscle, Skeletal/metabolism , Case-Control Studies , Adolescent , Real-Time Polymerase Chain Reaction , Circulating MicroRNA/bloodABSTRACT
Pancreatic cancer, an exceptionally malignant tumor of the digestive system, presents a challenge due to its lack of typical early symptoms and highly invasive nature. The majority of pancreatic cancer patients are diagnosed when curative surgical resection is no longer possible, resulting in a poor overall prognosis. In recent years, the rapid progress of Artificial intelligence (AI) in the medical field has led to the extensive utilization of machine learning and deep learning as the prevailing approaches. Various models based on AI technology have been employed in the early screening, diagnosis, treatment, and prognostic prediction of pancreatic cancer patients. Furthermore, the development and application of three-dimensional visualization and augmented reality navigation techniques have also found their way into pancreatic cancer surgery. This article provides a concise summary of the current state of AI technology in pancreatic cancer and offers a promising outlook for its future applications.
ABSTRACT
Objective: Acute pancreatitis (AP) is a process of acute inflammation and cell damage of the pancreas. Gallstones and alcohol abuse are the most common cause for AP. Drug-induced pancreatitis (DIP), accounting for less than 3% of the AP, has become increasingly recognized as an additional and vitally important etiology of acute pancreatitis. Sertraline is an antidepressant of the selective serotonin reuptake inhibitor (SSRI)class that has a range of side effects even when used at the recommended dose. A recognized but rare association in teenagers is acute pancreatitis. The report is of a 15-year-old male teenager with a history of depression who developed acute pancreatitis following self-overdose of his sertraline prescription. Case Report: A 15-year-old teenager with an overdose of sertraline, which was the only medication he took, presented abdominal pain, nausea, and vomiting. The common causes of alcohol consumption, gallstones, biliary duct obstruction, malignancy, trauma, hypertriglyceridemia, and hypercalcemia were eliminated. The increased level of amylase and parenchymal edema of the pancreas revealed in computed tomography supported the diagnosis of acute pancreatitis. After discontinuation of the drug and conventional acute pancreatitis treatment, he recovered evenly. Conclusion: With the increasing use of antidepressant medications in patients of teenagers, this report is a reminder that clinicians should be aware of the association between SSRIs such as sertraline, particularly in cases of overdose, and the development of acute pancreatitis.
ABSTRACT
OBJECTIVES: To differentiate high-grade from low-grade clear cell renal cell carcinoma (ccRCC) using diffusion-relaxation correlation spectroscopic imaging (DR-CSI) spectra in an equal separating analysis. METHODS: Eighty patients with 86 pathologically confirmed ccRCCs who underwent DR-CSI were enrolled. Two radiologists delineated the region of interest. The spectrum was derived based on DR-CSI and was further segmented into multiple equal subregions from 2*2 to 9*9. The agreement between the 2 radiologists was assessed by the intraclass correlation coefficient (ICC). Logistic regression was used to establish the regression model for differentiation, and 5-fold cross-validation was used to evaluate its accuracy. McNemar's test was used to compare the diagnostic performance between equipartition models and the traditional parameters, including the apparent diffusion coefficient (ADC) and T2 value. RESULTS: The inter-reader agreement decreased as the divisions in the equipartition model increased (overall ICC ranged from 0.859 to 0.920). The accuracy increased from the 2*2 to 9*9 equipartition model (0.68 for 2*2, 0.69 for 3*3 and 4*4, 0.70 for 5*5, 0.71 for 6*6, 0.78 for 7*7, and 0.75 for 8*8 and 9*9). The equipartition models with divisions >7*7 were significantly better than ADC and T2 (vs ADC: P = .002-.008; vs T2: P = .001-.004). CONCLUSIONS: The equipartition method has the potential to analyse the DR-CSI spectrum and discriminate between low-grade and high-grade ccRCC. ADVANCES IN KNOWLEDGE: The evaluation of DR-CSI relies on prior knowledge, and how to assess the spectrum derived from DR-CSI without prior knowledge has not been well studied.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Spectrum Analysis , Diagnostic Imaging , Cell DifferentiationABSTRACT
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, and accurate grading is crucial for prognosis and treatment selection. Biopsy is the reference standard for grading, but MRI methods can improve and complement the grading procedure. PURPOSE: Assess the performance of diffusion relaxation correlation spectroscopic imaging (DR-CSI) in grading ccRCC. STUDY TYPE: Prospective. SUBJECTS: 79 patients (age: 58.1 +/- 11.5 years; 55 male) with ccRCC confirmed by histopathology (grade 1, 7; grade 2, 45; grade 3, 18; grade 4, 9) following surgery. FIELD STRENGTH/SEQUENCE: 3.0 T MRI scanner. DR-CSI with a diffusion-weighted echo-planar imaging sequence and T2-mapping with a multi-echo spin echo sequence. ASSESSMENT: DR-CSI results were analyzed for the solid tumor regions of interest using spectrum segmentation with five sub-region volume fraction metrics (VA , VB , VC , VD , and VE ). The regulations for spectrum segmentation were determined based on the D-T2 spectra of distinct macro-components. Tumor size, voxel-wise T2, and apparent diffusion coefficient (ADC) values were obtained. Histopathology assessed tumor grade (G1-G4) for each case. STATISTICAL TESTS: One-way ANOVA or Kruskal-Wallis test, Spearman's correlation (coefficient, rho), multivariable logistic regression analysis, receiver operating characteristic curve analysis, and DeLong's test. Significance criteria: P < 0.05. RESULTS: Significant differences were found in ADC, T2, DR-CSI VB , and VD among the ccRCC grades. Correlations were found for ccRCC grade to tumor size (rho = 0.419), age (rho = 0.253), VB (rho = 0.553) and VD (rho = -0.378). AUC of VB was slightly larger than ADC in distinguishing low-grade (G1-G2) from high-grade (G3-G4) ccRCC (0.801 vs. 0.762, P = 0.406) and G1 from G2 to G4 (0.796 vs. 0.647, P = 0.175), although not significant. Combining VB , VD , and VE had better diagnostic performance than combining ADC and T2 for differentiating G1 from G2-G4 (AUC: 0.814 vs 0.643). DATA CONCLUSION: DR-CSI parameters are correlated with ccRCC grades, and may help to differentiate ccRCC grades. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 2.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Male , Middle Aged , Aged , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/pathology , Prospective Studies , Magnetic Resonance Imaging , Diffusion Magnetic Resonance Imaging/methods , Neoplasm Grading , Retrospective StudiesABSTRACT
By inducing CO2-pulsed discharges within microchannel bubbles and regulating thus-forming plasma microbubbles, we observe high-performance, catalyst-free coformation of hydrogen peroxide (H2O2) and oxalate directly from CO2 and water. With isotope-labeled C18O2 as the feedstock, peaks of H218O16O and H216O2 observed by ex situ surface-enhanced Raman spectra indicate that single-atom oxygen (O) from CO2 dissociations and H2O-derived OH radicals both contribute to H2O2 formation. The global plasma chemistry modeling suggests that high-density, energy-intense electron supply enables high-density CO2- (aq) and HCO2- (aq) formation and their subsequent coupling to produce oxalate. The enhanced solvation of CO2, facilitated by the efficient transport of CxOy ionic species and CO, is demonstrated as a crucial benefit of spark discharges interacting with water at the bubble interface. We expect this plasma microbubble approach to provide a novel power-to-chemical avenue to convert CO2 into valuable H2O2 and oxalic acid platform chemicals, thus leveraging renewable energy resources.
ABSTRACT
Gastrointestinal (GI) cancers are the most common types of tumors worldwide. The lack of cancer biomarkers and targeted drug resistance are barriers to achieving effective cancer therapy. Low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane protein that has multiple functions due to its ability to recognize different ligands; however, the role of LRP1 in GI cancer cells remains unclear. The present study aimed to investigate the role of LRP1 in GI tumors. The Cancer Genome Atlas database was used to analyze the potential correlation between expression of LRP1 and prognosis in patients with GI cancer. Bioinformatics analysis was utilized and the expression of LRP1 was simultaneously validated in GI cancer at the cellular level through western blot experiments. LRP1 was expressed at high levels in HGC-27, HepG2 and BxPC-3 cells. LRP1 expression in GI cancer cells was knocked down using lentivirus-mediated shRNA and the effects on biological functions were observed. LRP1 knockdown suppressed the proliferation, invasion and migration of GI cancer cells. LRP1 knockdown inhibited CD36 gene expression in HepG2 and BxPC-3 cells. LRP1 knockdown inhibited the proliferation, invasion and migration of GI cancer cells, suggesting that LRP1 may be a novel target for treatment of GI tumors.
ABSTRACT
BACKGROUND: Accumulating evidences have demonstrated that overwhelming inflammation occurs in the process of Coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVM). No specific therapy is available. More than an effective Janus-associated kinase (JAK) inhibiter, ruxolitinib exerts a critical role in the inflammatory diseases. In this study, we investigated the potential effect of ruxolitinib on CVB3-induced acute viral myocarditis. METHOD: In vivo, BALB/c mice were intraperitoneally injected of CVB3, treated of a successive gavage of ruxolitinib for seven days, and subjected to a series of analysis. In vitro, primary bone marrow-derived macrophages (BMDMs) and cardiac fibroblasts were isolated, cultured, treated, harvested and finally detected. RESULTS: In vivo, acute viral myocarditis was successfully induced by the injection of CVB3 characterized by impaired cardiac function, predominant infiltration of inflammatory cells, necroptosis of myocardium, great increase of cardiac troponin I (cTnI) and cytokine levels, replication of CVB3, and excessive activation of JAK-STAT pathways. Oral administration of ruxolitinib suppressed the activation of JAK-STAT pathway in a dosage-dependent way, lessened the infiltration of inflammatory cells and necroptosis of myocardium, reduced the levels of cTnI and cytokines, and finally alleviated CVB3-induced cardiac dysfunction, with the reduced production of type I interferon and no promising effect on the replication of CVB3. In vitro, the treatment of ruxolitinib inhibited the activation of JAK-STAT pathway and increase of multiple cytokines mRNA levels in BMDMs and had no protective effect against CVB3 replication in cardiac fibroblasts. CONCLUSIONS: Our study suggested that ruxolitinib ameliorated CVB3-induced AVM by inhibiting the activation of JAK-STAT pathway, infiltration of inflammatory cells and necroptosis of myocardium, which may provide a novel strategy for AVM therapy.
ABSTRACT
Pancreatic cancer is one of the highly malignant gastrointestinal tumors in humans, and patients suffer from cancer pain in the process of cancer. Most patients suffer from severe pain in the later stages of the disease. The latest studies have shown that the main cause of pain in patients with pancreatic cancer is neuroinflammation caused by tumor cells invading nerves and triggering neuropathic pain on this basis, which is believed to be the result of nerve invasion. Peripheral nerve invasion (PNI), defined as the presence of cancer cells along the nerve or in the epineurial, perineural, and endoneurial spaces of the nerve sheath, is a special way for cancer to spread to distant sites. However, due to limited clinical materials, the research on the mechanism of pancreatic cancer nerve invasion has not been carried out in depth. In addition, perineural invasion is considered to be one of the underlying causes of recurrence and metastasis after pancreatectomy and an independent predictor of prognosis. This article systematically reviewed the neural invasion of pancreatic cancer through bioinformatics analysis, clinical manifestations and literature reviews.
ABSTRACT
USP28 contributes to tumorigenesis through modulating the lifespan of oncogenic factors such as c-Myc and ΔNp63, and it has been identified as a potential target for anti-cancer drug development. Currently, although quite a number of USP28 inhibitors have been developed, they all are still in preclinical research stage. Besides, none of them exhibits satisfying inhibition selectivity against USP28 over its closest homologue USP25. Here in this manuscript, a high-throughput screening aiming to discover USP28 inhibitors with novel scaffold and enhanced inhibition selectivity were conducted. After the primary screening and the second round of validation, Otilonium Bromide, an approved drug for treating irritable bowel syndrome, was identified to inhibit USP28's activity with the IC50 value at 6.90 ± 0.90 µM. Besides, the drug exhibits a 3-4 folds inhibition selectivity against USP28 over USP25. According to the enzymatic kinetics analysis data and the hydrogen-deuterium exchange mass spectrometry results, Otilonium Bromide could bind to the allosteric pocket of USP28 and inhibit its activity in a reversible and non-competitive mode. The following performed cell-based assays revealed that the drug could cause cytotoxicity against human colorectal cancer cells and lung squamous carcinoma cells potentially through down-regulating USP28's oncogenic substrates c-Myc and/or ΔNp63. Meanwhile, since Otilonium Bromide has been found to preferentially distribute to gastrointestinal tissues, we then evaluated its potential in the combination treatment of colorectal cancer cells with Regorafenib, which is an approved drug for colorectal cancer therapy. As expected, Otilonium Bromide could significantly enhance the sensitivity of colorectal cancer cells to Regorafenib.
Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Humans , Quaternary Ammonium Compounds , Antineoplastic Agents/pharmacology , Ubiquitin Thiolesterase , Cell Line , Colorectal Neoplasms/drug therapyABSTRACT
Oncolytic viruses have recently been proven to be an effective and promising cancer therapeutic strategy, but there is rare data about oncolytic therapy in esophageal squamous cell carcinoma (ESCC), especially oncolytic measles virotherapy. Therefore, this study aimed to explore whether the recombinant measles virus vaccine strain rMV-Hu191 has an oncolytic effect against ESCC cells in vitro and in vivo and elucidate the underlying mechanisms. Our results showed that rMV-Hu191 could efficiently replicate in and kill ESCC cells through caspase-3/GSDME-mediated pyroptosis. Mechanistically, rMV-Hu191 triggers mitochondrial dysfunction to induce pyroptosis, which is mediated by BAK (BCL2 antagonist/killer 1) or BAX (BCL2 associated X). Further analysis revealed that rMV-Hu191 activates inflammatory signaling in ESCC cells, which may enhance the oncolytic efficiency. Moreover, intratumoral injection of rMV-Hu191 induced dramatic tumor regression in an ESCC xenograft model. Collectively, these findings imply that rMV-Hu191 exhibits an antitumor effect through BAK/BAX-dependent caspase-3/GSDME-mediated pyroptosis and provides a potentially promising new therapy for ESCC treatment.
ABSTRACT
Introduction: Early and accurate identification of pathogens is essential for improved outcomes in patients with viral encephalitis (VE) and/or viral meningitis (VM). Methods: In our research, Metagenomic next-generation sequencing (mNGS) which can identify viral pathogens unbiasedly was performed on RNA and DNA to identify potential pathogens in cerebrospinal fluid (CSF) samples from 50 pediatric patients with suspected VEs and/or VMs. Then we performed proteomics analysis on the 14 HEV-positive CSF samples and another 12 CSF samples from health controls (HCs). A supervised partial least squaresdiscriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) model was performed using proteomics data. Results: Ten viruses in 48% patients were identified and the most common pathogen was human enterovirus (HEV) Echo18. 11 proteins overlapping between the top 20 DEPs in terms of P value and FC and the top 20 proteins in PLS-DA VIP lists were acquired. Discussion: Our result showed mNGS has certain advantages on pathogens identification in VE and VM and our research established a foundation to identify diagnosis biomarker candidates of HEV-positive meningitis based on MS-based proteomics analysis, which could also contribute toward investigating the HEV-specific host response patterns.
Subject(s)
Encephalitis, Viral , Enterovirus , Meningitis, Viral , Viruses , Humans , Child , Proteomics , Encephalitis, Viral/diagnosis , Viruses/genetics , Meningitis, Viral/diagnosis , Enterovirus/genetics , High-Throughput Nucleotide Sequencing , Metagenomics , Sensitivity and SpecificityABSTRACT
Shape-stable phase change materials (ss-PCMs) are extensively applied in renewable energy storage. The core for realizing high latent heat and good thermal stability of ss-PCMs is the designation of suitable supporting skeletons that can effectively preserve the PCMs from leaking out. In this study, ss-PCMs impregnated by D-mannitol were prepared using a waste yeast-derived carbon (YC) as the support material. YC possesses a large surface area (669.90 m2/g), which can provide sufficient phase transition space and nucleation sites for D-mannitol. The results indicated that a reduced supercooling of 44.76 °C for YC/D-mannitol ss-PCMs can be realized. The ss-PCMs also exhibited good cycling stability, with latent heat loss rates of 4.00% and 2.15% after 200 thermal cycles. We further demonstrate that YC provides restricted space for mannitol to inhibit the supercooling mechanism. The YC/D-mannitol ss-PCMs exhibited great promise for solar heat storage and industrial waste heat recovery in the medium temperature domain.
ABSTRACT
High-fat diet (HFD) intake provokes obesity and cardiac anomalies. Recent studies have found that ferroptosis plays a role in HFD-induced cardiac injury, but the underlying mechanism is largely unclear. Ferritinophagy is an important part of ferroptosis that is regulated by nuclear receptor coactivator 4 (NCOA4). However, the relationship between ferritinophagy and HFD-induced cardiac damage has not been explored. In this study, we found that oleic acid/palmitic acid (OA/PA) increased the level of ferroptotic events including iron and ROS accumulation, upregulation of PTGS2 mRNA and protein levels, reduced SOD and GSH levels, and significant mitochondrial damage in H9C2 cells, which could be reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Intriguingly, we found that the autophagy inhibitor 3-methyladenine mitigated OA/PA-induced ferritin downregulation, iron overload and ferroptosis. OA/PA increased the protein level of NCOA4. Knockdown of NCOA4 by SiRNA partly reversed the reduction in ferritin, mitigated iron overload and lipid peroxidation, and subsequently alleviated OA/PA-induced cell death, indicating that NCOA4-mediated ferritinophagy was required for OA/PA-induced ferroptosis. Furthermore, we demonstrated that NCOA4 was regulated by IL-6/STAT3 signaling. Inhibition or knockdown of STAT3 effectively reduced NCOA4 levels to protect H9C2 cells from ferritinophagy-mediated ferroptosis, whereas STAT3 overexpression by plasmid appeared to increase NCOA4 expression and contribute to classical ferroptotic events. Consistently, phosphorylated STAT3 upregulation, ferritinophagy activation, and ferroptosis induction also occurred in HFD-fed mice and were responsible for HFD-induced cardiac injury. In addition, we found evidence that piperlongumine, a natural compound, effectively reduced phosphorylated STAT3 levels to protect cardiomyocytes from ferritinophagy-mediated ferroptosis both in vitro and in vivo. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis was one of the critical mechanisms contributing to HFD-induced cardiac injury. The STAT3/NCOA4/FTH1 axis might be a novel therapeutic target for the treatment of HFD-induced cardiac injury.