FABP4-mediated lipid metabolism promotes TNBC progression and breast cancer stem cell activity.

Metabolic remodeling is a pivotal feature of cancer, with cancer stem cells frequently showcasing distinctive metabolic behaviors. Nonetheless, understanding the metabolic intricacies of triple-negative breast cancer (TNBC) and breast cancer stem cells (BCSCs) has remained elusive. In this study, we meticulously characterized the metabolic profiles of TNBC and BCSCs and delved into their potential implications for TNBC treatment. Our findings illuminated the robust lipid metabolism activity within TNBC tumors, especially in BCSCs. Furthermore, we discovered that Fabp4, through its mediation of fatty acid uptake, plays a crucial role in regulating TNBC lipid metabolism. Knocking down Fabp4 or inhibiting its activity significantly suppressed TNBC tumor progression in both the MMTV-Wnt1 spontaneous TNBC model and the TNBC patient-derived xenograft model. Mechanistically, Fabp4's influence on TNBC tumor progression was linked to its regulation of mitochondrial stability, the CPT1-mediated fatty acid oxidation process, and ROS production. Notably, in a high-fat diet model, Fabp4 deficiency proved to be a substantial inhibitor of obesity-accelerated TNBC progression. Collectively, these findings shed light on the unique metabolic patterns of TNBC and BCSCs, underscore the biological significance of Fabp4-mediated fatty acid metabolism in governing TNBC progression, and offer a solid theoretical foundation for considering metabolic interventions in breast cancer treatment. SIGNIFICANCE: Triple-negative breast cancer progression and breast cancer stem cell activity can be restricted by targeting a critical regulator of lipid responses, FABP4.

Preliminary study on the mechanism by which exosomes derived from human exfoliated deciduous teeth improve the proliferation and osteogenic inhibitory effect of glucocorticoid-induced BMSCs.

BACKGROUND: Steroid-induced osteonecrosis of the femoral head (SONFH) is a disease characterized by a collapsed femoral head caused by the overuse of glucocorticoids. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) is an important pathological feature of SONFH. In this study, we investigated whether exosomes from SHEDs (stem cells from human exfoliated deciduous teeth) have a therapeutic effect on glucocorticoid-induced inhibition of proliferation and osteogenesis in BMSCs, and elucidated the underlying mechanisms involved. METHODS: Primary dental pulp cells were isolated and cultured from human deciduous tooth pulp, SHEDs were isolated and purified by the limiting dilution method and exosomes were isolated from the supernatants of SHEDs by ultracentrifugation. The cell surface markers CD31, CD34, CD45, CD73, CD90 and CD105 were detected by flow cytometry. A Cell-Counting-Kit-8 assay was used to detect cell activity. ALP and Alizarin Red staining were used to identify osteogenic differentiation ability, and exosomes were identified using transmission electron microscopy, NanoFCM and Western blotting. PKH67 fluorescence was used to track the uptake of exosomes by BMSCs. Transcriptome analysis combined with quantitative real-time PCR was used to explore the underlying mechanism involved. RESULTS: Exosomes secreted by SHEDs can be endocytosed by BMSCs, and can partially reverse the inhibitory effects of glucocorticoids on the viability and osteogenic differentiation of BMSCs. Transcriptome sequencing analysis revealed that the differentially expressed mRNAs regulated by SHED-derived exosomes were enriched mainly in signaling pathways such as the apoptosis pathway, the PI3K-Akt signaling pathway, the Hippo signaling pathway and the p53 signaling pathway. qPCR showed that SHED-derived exosomes reversed the dexamethasone-induced upregulation of HGF and ITGB8 expression and the inhibition of EFNA1 expression, but further increased the dexamethasone-induced downregulation of IL7 expression. In conclusion, SHED-derived exosomes partially reversed the inhibitory effects of glucocorticoids on BMSC proliferation and osteogenesis by inhibiting the expression of HGF, ITGB8 and IL7, and upregulating the expression of EFNA1.

Quantitative Analysis of Hemodynamic Changes in Branch Arteries Covered by Flow Diverters.

BACKGROUND AND OBJECTIVES: Understanding post-treatment hemodynamic alterations and their association with the patency of covered branch arteries is limited. This study aims to identify hemodynamic changes after flow diverter stenting and investigate their correlation with the patency status of covered branch arteries. METHODS: All patients treated with pipeline embolization device for anterior cerebral artery aneurysms at our center between 2016 and 2020 were screened for inclusion. Quantitative digital subtraction angiography was used to analyze changes in hemodynamic parameters pre- and post-stenting. The patency status of covered branch arteries after stenting was categorized as either patent or flow impairment (defined as artery stenosis or occlusion). RESULTS: A total of 71 patients, encompassing 89 covered branch arteries, were enrolled. Flow impairment was observed in 11.2% (10/89) of the branches. The mean transit time and full width at half maximum (FWHM) in covered branches were significantly prolonged post-stenting (P = .004 and .023, respectively). Flow-impaired branch arteries exhibited hemodynamic shifts contrary to those in patent branch arteries. Specifically, flow-impaired branches showed marked reductions in time to peak, FWHM, and mean transit time (decreases of 32.8%, 32.6%, and 29%, respectively; P = .006, .002, and .002, respectively). Further multivariate analysis revealed that reductions in FWHM in the branches (odds ratio = 0.97, 95% CI: 0.95-0.99, P = .007) and smoking (odds ratio = 14.5, 95% CI: 1.39-151.76, P = .026) were independent predictors of flow impairment of covered branches. CONCLUSION: Pipeline embolization device stenting can cause a reduction in blood flow in branch arteries. Compared with patent branches, flow-impaired branches exhibit an increase in blood flow velocity after stenting. Smoking and ΔFWHM in the covered branches indicate flow impairment.

Analysis of vibrational dynamics in cell-substrate interactions using nanopipette electrochemical sensors.

Cell-substrate interaction plays a critical role in determining the mechanical status of living cell membrane. Changes of substrate surface properties can significantly alter the cell mechanical microenvironment, leading to mechanical changes of cell membrane. However, it is still difficult to accurately quantify the influence of the substrate surface properties on the mechanical status of living cell membrane without damage. This study addresses the challenge by using an electrochemical sensor made from an ultrasmall quartz nanopipette. With the tip diameter less than 100 nm, the nanopipette-based sensor achieves highly sensitive, noninvasive and label-free monitoring of the mechanical status of single living cells by collecting stable cyclic membrane oscillatory signals from continuous current versus time traces. The electrochemical signals collected from PC12 cells cultured on three different substrates (bare ITO (indium tin oxides) glass, hydroxyl modified ITO glass, amino modified ITO glass) indicate that the microenvironment more favorable for cell adhesion can increase the membrane stiffness. This work provides a label-free electrochemical approach to accurately quantify the mechanical status of single living cells in real-time, which may help to better understand the relationship between the cell membrane and the extra cellular matrix.

Amide proton transfer imaging has added value for predicting extraprostatic extension in prostate cancer patients.

Background: Prostate cancer invades the capsule is a key factor in selecting appropriate treatment methods. Accurate preoperative prediction of extraprostatic extension (EPE) can help achieve precise selection of treatment plans. Purpose: The aim of this study is to verify the diagnostic efficacy of tumor size, length of capsular contact (LCC), apparent diffusion coefficient (ADC), and Amide proton transfer (APT) value in predicting EPE. Additionally, the study aims to investigate the potential additional value of APT for predicting EPE. Method: This study include 47 tumor organ confined patients (age, 64.16 ± 9.18) and 50 EPE patients (age, 61.51 ± 8.82). The difference of tumor size, LCC, ADC and APT value between groups were compared. Binary logistic regression was used to screen the EPE predictors. The receiver operator characteristic curve analysis was performed to assess the diagnostic performance of variables for predicting EPE. The diagnostic efficacy of combined models (model I: ADC+LCC+tumor size; model II: APT+LCC+tumor size; and model III: APT +ADC+LCC+tumor size) were also analyzed. Results: APT, ADC, tumor size and the LCC were independent predictors of EPE. The area under the curve (AUC) of APT, ADC, tumor size and the LCC were 0.752, 0.665, 0.700 and 0.756, respectively. The AUC of model I, model II, and model III were 0.803, 0.845 and 0.869, respectively. The cutoff value of APT, ADC, tumor size and the LCC were 3.65%, 0.97×10-3mm2/s, 17.30mm and 10.78mm, respectively. The sensitivity/specificity of APT, ADC, tumor size and the LCC were 76%/89.4.0%, 80%/59.6%, 54%/78.9%, 72%/66%, respectively. The sensitivity/specificity of model I, Model II and Model III were 74%/72.3%, 82%/72.5% and 84%/80.9%, respectively. Data conclusion: Amide proton transfer imaging has added value for predicting EPE. The combination model of APT balanced the sensitivity and specificity.

Diagnosis of intracranial aneurysms by computed tomography angiography using deep learning-based detection and segmentation.

BACKGROUND: Detecting and segmenting intracranial aneurysms (IAs) from angiographic images is a laborious task. OBJECTIVE: To evaluates a novel deep-learning algorithm, named vessel attention (VA)-Unet, for the efficient detection and segmentation of IAs. METHODS: This retrospective study was conducted using head CT angiography (CTA) examinations depicting IAs from two hospitals in China between 2010 and 2021. Training included cases with subarachnoid hemorrhage (SAH) and arterial stenosis, common accompanying vascular abnormalities. Testing was performed in cohorts with reference-standard digital subtraction angiography (cohort 1), with SAH (cohort 2), acquired outside the time interval of training data (cohort 3), and an external dataset (cohort 4). The algorithm's performance was evaluated using sensitivity, recall, false positives per case (FPs/case), and Dice coefficient, with manual segmentation as the reference standard. RESULTS: The study included 3190 CTA scans with 4124 IAs. Sensitivity, recall, and FPs/case for detection of IAs were, respectively, 98.58%, 96.17%, and 2.08 in cohort 1; 95.00%, 88.8%, and 3.62 in cohort 2; 96.00%, 93.77%, and 2.60 in cohort 3; and, 96.17%, 94.05%, and 3.60 in external cohort 4. The segmentation accuracy, as measured by the Dice coefficient, was 0.78, 0.71, 0.71, and 0.66 for cohorts 1-4, respectively. VA-Unet detection recall and FPs/case and segmentation accuracy were affected by several clinical factors, including aneurysm size, bifurcation aneurysms, and the presence of arterial stenosis and SAH. CONCLUSIONS: VA-Unet accurately detected and segmented IAs in head CTA comparably to expert interpretation. The proposed algorithm has significant potential to assist radiologists in efficiently detecting and segmenting IAs from CTA images.

Biosynthesis of fungal terpenoids.

Covering: up to August 2023Terpenoids, which are widely distributed in animals, plants, and microorganisms, are a large group of natural products with diverse structures and various biological activities. They have made great contributions to human health as therapeutic agents, such as the anti-cancer drug paclitaxel and anti-malarial agent artemisinin. Accordingly, the biosynthesis of this important class of natural products has been extensively studied, which generally involves two major steps: hydrocarbon skeleton construction by terpenoid cyclases and skeleton modification by tailoring enzymes. Additionally, fungi (Ascomycota and Basidiomycota) serve as an important source for the discovery of terpenoids. With the rapid development of sequencing technology and bioinformatics approaches, genome mining has emerged as one of the most effective strategies to discover novel terpenoids from fungi. To date, numerous terpenoid cyclases, including typical class I and class II terpenoid cyclases as well as emerging UbiA-type terpenoid cyclases, have been identified, together with a variety of tailoring enzymes, including cytochrome P450 enzymes, flavin-dependent monooxygenases, and acyltransferases. In this review, our aim is to comprehensively present all fungal terpenoid cyclases identified up to August 2023, with a focus on newly discovered terpenoid cyclases, especially the emerging UbiA-type terpenoid cyclases, and their related tailoring enzymes from 2015 to August 2023.

CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis.

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 (cluster of differentiation 147) in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE-/-) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor-associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest-specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE-/- mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5-dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

Erianin suppressed lung cancer stemness and chemotherapeutic sensitivity via triggering ferroptosis.

The previous research has focused on the suppressive effects of Erianin on tumor progression, but its impact on cancer stemness has not been reported. This study aimed to investigate the effects of Erianin on lung cancer stemness. First, we screened various concentrations Erianin to ensure that it did not affect lung cancer cell viability. Subsequently, we found that Erianin significantly attenuated lung cancer stemness through various analyses, including qRT-PCR, western blot, sphere-formation, and ALDH activity detection. Furthermore, Erianin was shown to enhance chemosensitivity of lung cancer cells. Mechanistically, three inhibitors (cell apoptosis inhibitor, necrosis inhibitor, and ferroptosis inhibitor) were added into lung cancer cells with Erianin treatment, respectively, and we found that Erianin mainly suppressed lung cancer stemness through ferroptosis. Taken together, this study reveals that Erianin has the potential to suppress lung cancer stemness and could be a valuable chemotherapeutic enhancer for lung cancer.

Interfacial Organization and Forces Arising from Epithelial-Cancerous Monolayer Interactions.

The interfacial interactions between epithelia and cancer cells have profound relevance for tumor development and metastasis. Through monolayer confrontation of MCF10A (nontumorigenic human breast epithelial cells) and MDA-MB-231 (human epithelial breast cancer cells) cells, we investigate the epithelial-cancerous interfacial interactions at the tissue level. We show that the monolayer interaction leads to competitive interfacial morphodynamics and drives an intricate spatial organization of MCF10A cells into multicellular finger-like structures, which further branch into multiple subfinger-like structures. These hierarchical interfacial structures penetrate the cancer monolayer and can spontaneously segregate or even envelop cancer cell clusters, consistent with our theoretical prediction. By tracking the substrate displacements via embedded fluorescent nanobeads and implementing nanomechanical modeling that combines atomic force microscopy and finite element simulations, we computed mechanical force patterns, including traction forces and monolayer stresses, caused by the monolayer interaction. It is found that the heterogeneous mechanical forces accumulated in the monolayers are able to squeeze cancer cells, leading to three-dimensional interfacial bulges or cell extrusion, initiating the p53 apoptosis signaling pathways of cancer cells. We reveal that intercellular E-cadherin and P-cadherin of epithelial cells differentially regulate the interfacial organization including migration speed, directionality, spatial correlation, F-actin alignment, and subcellular protrusions of MCF10A cells; whereas E-cadherin governs interfacial geometry that is relevant to force localization and cancer cell extrusion, P-cadherin maintains interfacial integrity that enables long-range force transmission. Our findings suggest that the collaborative molecular and mechanical behaviors are crucial for preventing epithelial tissues from undergoing tumor invasion.

Extracellular vesicle-derived circHIPK3: Novel diagnostic biomarker for lung cancer.

PURPOSE: Lung cancer (LC) is a common malignancy worldwide. A great number of circular RNAs (circRNAs) have been identified that serve crucial roles in cancer development. Extracellular vesicles (EVs) and their contents have been shown to be biomarkers for the diagnosis and prognosis of LC. Thus, we intended to clarify the functional role of EVs-derived circRNA homology domain interacting protein kinase 3 (EVs-circHIPK3) and its underlying mechanism of action. MATERIAL AND METHODS: Bioinformatics analysis was performed to validate the potential of partially circulating HIPK3 in LC diagnosis. EVs were isolated by polyethylene glycol (PEG) precipitation from plasma of 52 LC patients and 30 healthy controls. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to evaluate the expressions of candidate circRNAs (circHIPK3) and microRNA-637 (miR-637, a target of circHIPK3). RESULTS: CircHIPK3 is significantly up-regulated in LC, while miR-637 expression is significantly reduced (p â€‹< â€‹0.05). Receiver operating characteristic (ROC) curve analysis, based on the expression of EVs-circHIPK3, allowed us to distinguish LC from healthy controls (area under the curve, AUC 0.897). CONCLUSIONS: Taken together, our study shows that EV-derived circHIPK3 can serve as a promising biomarker for LC patient diagnosis. However, the downstream mRNA of the circHIPK3/miR-637 axis requires further exploration to enrich our understanding of circHIPK3's mechanism in LC.

Association of glyphosate exposure with multiple adverse outcomes and potential mediators.

Glyphosate (GLY) is a widely used herbicide with potential adverse effects on public health. However, the current epidemiological evidence is limited. This study aimed to investigate the potential associations between exposure to GLY and multiple health outcomes. The data on urine GLY concentration and nine health outcomes, including type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease (CVD), obesity, chronic kidney disease (CKD), hepatic steatosis, cancers, chronic obstructive pulmonary disease (COPD), and neurodegenerative diseases (NGDs), were extracted from NHANES (2013-2016). The associations between GLY exposure and each health outcome were estimated using reverse-scale Cox regression and logistic regression. Furthermore, mediation analysis was conducted to identify potential mediators in the significant associations. The dose-response relationships between GLY exposure with health outcomes and potential mediators were analyzed using restricted cubic spline (RCS) regression. The findings of the study revealed that individuals with higher urinary concentrations of GLY had a higher likelihood of having T2DM, hypertension, CVD and obesity (p < 0.001, p = 0.005, p < 0.001 and p = 0.005, respectively). In the reverse-scale Cox regression, a notable association was solely discerned between exposure to GLY and the risk of T2DM (adjusted HR = 1.22, 95% CI: 1.10, 1.36). Consistent outcomes were also obtained via logistic regression analysis, wherein the adjusted OR and 95% CI for T2DM were determined to be 1.30 (1.12, 1.52). Moreover, the present investigation identified serum high-density lipoprotein cholesterol (HDL) as a mediator in this association, with a mediating effect of 7.14% (p = 0.040). This mediating effect was further substantiated by RCS regression, wherein significant dose-response associations were observed between GLY exposure and an increased risk of T2DM (p = 0.002) and reduced levels of HDL (p = 0.001). Collectively, these findings imply an association between GLY exposure and an increased risk of T2DM in the general adult population.

Smart Nanoplatform for Visualizing Hydrogen Sulfide and Amplifying Oxidative Stress to Tumor Apoptosis.

Oxidative stress is involved in various signaling pathways and serves a key role in inducing cell apoptosis. Therefore, it is significant to monitor oxidative stress upon drug release for the assessment of therapeutic effects in cancer cells. Herein, a glutathione (GSH)-responsive surface-enhanced Raman scattering (SERS) nanoplatform is proposed for ultra-sensitively monitoring the substance related with oxidative stress (hydrogen sulfide, H2S), depleting reactive sulfur species and releasing anticancer drugs to amplify oxidative stress for tumor apoptosis. The Au@Raman reporter@Ag (Au@M@Ag) nanoparticles, where a 4-mercaptobenzonitrile molecule as a Raman reporter was embedded between layers of gold and silver to obtain sensitive SERS response, were coated with a covalent organic framework (COF) shell to form a core-shell structure (Au@M@Ag@COFs) as the SERS nanoplatform. The COF shell loading doxorubicin (DOX) of Au@M@Ag@COFs exhibited the GSH-responsive degradation capacity to release DOX, and its Ag layer as the sensing agent was oxidized to Ag2S by H2S to result in its prominent changes in SERS signals with a low detection limit of 0.33 nM. Moreover, the releasing DOX can inhibit the generation of H2S to promote the production of reactive oxygen species, and the depletion of reactive sulfur species (GSH and H2S) in cancer cells can further enhance the oxidative stress to induce tumor apoptosis. Overall, the SERS strategy could provide a powerful tool to monitor the dynamic changes of oxidative stress during therapeutic processes in a tumor microenvironment.

Localizing the position of the Segond fracture bed under CT measurements to determine the functional tibial insertion of an anterolateral ligament.

Background: Many studies have confirmed the existence of ligament structures in the anterolateral region of the knee that maintain rotational stability of the knee joint, namely, the anterolateral ligament (ALL). Most scholars believe that knee joint reconstruction should be considered during revision surgery and a high level of pivot displacement test (stage 2 or 3). During ALL reconstruction, the choice of ligament reconstruction sites affects the success rate and prognosis of the operation. Therefore, the choice of ligament reconstruction sites is particularly important. There is little research on the lateral ALL tibia insertion point, and most clinicians use the midpoint Gerdy's tubercle and fibular head as insertion points. However, the reconstruction effect is not ideal. Objective: This study aims to measure the position of the Segond fracture bed on CT images to determine the ALL position of the tibia. Method: To determine the position of the Segond fracture bone bed, the CT AM Volume Share 2 system was used to manually measure the position of bone fragments in 23 Segond fracture patients. Using the highest point of Gerdy's tubercle in the CT axial slices and the outermost point of the fibular head in the CT axial slices as reference points, the direction and angle of the CT slices were adjusted to ensure that the highest point of the Gerdy tubercle, the outermost point of the fibular head, and the center of Segond fracture bed were in the same sagittal slice. A CT sagittal slice measures the vertical distance from the center of the Segond fracture bed to the Gerdy-fibular line segment (G-F line segment), which is the line connecting the highest point of the segment to the outermost point of the fibula. The distance from the vertical point at the center of the Segond fracture bed of the G-F line to the highest point of the Gerdy tubercle was measured. All measurements were performed using the same measurement standard and were expressed as a percentage of the length of the G-F line. The measured results were statistically analyzed using SPSS 25.0 descriptive statistical research methods. Results: The average length of the G-F segment measured on CT images was 39.6 ± 2.0 mm, and the average vertical length from the center of the Segond fracture bed to the G-F segment was 13.1 ± 1.1 mm, accounting for 33.2% ± 2.1% of the length of the G-F segment. The length from the vertical point of the fracture bed on the G-F line segment to the highest point of the Gerdy tubercle was 14.7 ± 1.3 mm, accounting for 37.1% ± 2.9% of the length of the G-F segment. Conclusion: Through the study of the CT measurement of the Segond fracture location, we obtained the location of the functional tibial insertion of ALL, which is different from the anatomical insertion of ALL and is more inclined to the Gerdy tubercle and above, which has reference value for the treatment of recovering the function of anterolateral ligament after reconstruction.

Amperometric Identification of Single Exosomes and Their Dopamine Contents Secreted by Living Cells.

Dopamine (DA) is an important neurotransmitter, which not only participates in the regulation of neural processes but also plays critical roles in tumor progression and immunity. However, direct identification of DA-containing exosomes, as well as quantification of DA in single vesicles, is still challenging. Here, we report a nanopipette-assisted method to detect single exosomes and their dopamine contents via amperometric measurement. The resistive-pulse current measured can simultaneously provide accurate information of vesicle translocation and DA contents in single exosomes. Accordingly, DA-containing exosomes secreted from HeLa and PC12 cells under different treatment modes successfully detected the DA encapsulation efficiency and the amount of exosome secretion that distinguish between cell types. Furthermore, a custom machine learning model was constructed to classify the exosome signals from different sources, with an accuracy of more than 99%. Our strategy offers a useful tool for investigating single exosomes and their DA contents, which facilitates the analysis of DA-containing exosomes derived from other untreated or stimulated cells and may open up a new insight to the research of DA biology.

A multi-channel responsive AuNP@COF core-shell nanoprobe for simultaneous subcellular profiling of multiple cancer biomarkers.

The abnormal change in the expression profile of multiple cancer biomarkers is closely related to tumor progression and therapeutic effect. Due to their low abundance in living cells and the limitations of existing imaging techniques, simultaneous imaging of multiple cancer biomarkers has remained a significant challenge. Here, we proposed a multi-modal imaging strategy to detect the correlated expression of multiple cancer biomarkers, MUC1, microRNA-21 (miRNA-21) and reactive oxygen (ROS) in living cells, based on a porous covalent organic framework (COF) wrapped gold nanoparticles (AuNPs) core-shell nanoprobe. The nanoprobe is functionalized with Cy5-labeled MUC1 aptamer, a ROS-responsive molecule (2-MHQ), and a miRNA-21-response hairpin DNA tagged by FITC as the reporters for different biomarkers. The target-specific recognition can induce the orthogonal molecular change of these reporters, producing fluorescence and Raman signals for imaging the expression profiles of membrane MUC1 (red fluorescence channel), intracellular miRNA-21 (green fluorescence channel), and intracellular ROS (SERS channel). We further demonstrate the capability of the cooperative expression of these biomarkers, along with the activation of NF-κB pathway. Our research provides a robust platform for imaging multiple cancer biomarkers, with broad potential applications in cancer clinical diagnosis and drug discovery.

Torsemide increases arsenic concentrations by inhibition of multidrug resistance protein 4 in arsenic trioxide treated acute promyelocytic leukemia patients.

Torsemide is commonly used to relieve edema during the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO). We explored the effect of torsemide on the plasma concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in APL patients treated with ATO and clarified its molecular mechanism in rats and cells. The study included 146 APL patients treated with ATO. 60（41.1 %) of these 146 patients were co-administered with torsemide. The treatment of torsemide increased plasma concentrations of iAs (P < 0.05) and DMAV (P < 0.05) in APL patients. The single co-administration of ATO and torsemide in rats significantly increased the plasma concentrations and AUC(0-t) of iAs (P < 0.05) and MMAV (P < 0.05), decreased the urinary excretion rates and the urine concentrations of iAs (P < 0.05) and DMAV (P < 0.05), and enhanced iAs (P < 0.05) and MMAV (P < 0.05) concentrations in the kidneys of rats. In addition, torsemide decreased the expression of multidrug resistance protein 4 (MRP4) in rat kidneys after 7 days of continuous co-administration (P < 0.05). We also treated MRP4-overexpressing HEK293T cells with ATO and different concentrations of torsemide. Torsemide markedly increased the concentrations of iAs, MMAV and DMAV by inhibiting MRP4 compared with ATO alone (P < 0.05). In conclusion, torsemide increased the plasma concentrations of arsenic metabolites in APL patients treated with ATO by inhibiting the transporter MRP4 in a dose-dependent manner.

Isolation of new compounds related to xyloketals biosynthesis implies an alternative pathway for furan-fused-chromene formation.

In fungi, there is a rare group of natural products harboring the 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene skeleton, represented by xyloketal B, which display a wide range of biological activities and have drawn significant attention. In this work, four new analogues simpliketals A-D (1-4), as well as two other new compounds simplilactones A and B (5 and 6), were isolated from Simplicillium sp. AHK071-01. Their structures were elucidated by extensive NMR spectroscopic methods, 13C NMR calculation, single-crystal X-ray diffraction, and ECD calculation. In addition, five known compounds (7-11) including alboatrin (7) were also obtained. Based on the structural similarity of the above compounds, we inferred that compounds 5, 6, and 8-11 might be biosynthetically related with 1-4 and 7, which allowed us to propose an alternative biosynthetic route to generate the furan-fused chromene skeleton of this class of compounds, instead of a previously presumed polyketide-terpenoid hybrid pathway. Finally, cytotoxicity assays showed that 1-4 exhibited weak inhibitory activity on PANC-1 cells and that 2 and 3 possessed moderate activity against SH-SY5Y cells.

Chromosome 11q13 amplification correlates with poor response and prognosis to PD-1 blockade in unresectable hepatocellular carcinoma.

Background & aims: Little is known about molecular biomarkers that predict the response and prognosis in unresectable hepatocellular carcinoma (HCC) treated with programmed death (PD)-1 inhibitors. Methods: A total of 62 HCC patients who underwent next-generation sequencing were retrospectively included in our department for this study. Patients with unresectable disease were subjected to systemic therapy. PD-1 inhibitors intervention (PD-1Ab) group and nonPD-1Ab group included 20 and 13 patients, respectively. Primary resistance was defined as initial on-treatment progression or progression with an initial stable disease of less than 6 months. Results: Chromosome 11q13 amplification (Amp11q13) was the most common copy number variation in our cohort. Fifteen (24.2%) patients harbored Amp11q13 in our dataset. Patients with Amp11q13 showed higher level of Des-γ-carboxy-prothrombin (DCP), tumor number and were more prone to be combined with portal vein tumor thrombosis (PVTT). In the PD-1Ab group, the proportion of progressive disease (PD) in patients with Amp11q13 was significantly higher than that in patients with nonAmp11q13 (100% vs 33.3%, P=0.03). In the nonPD-1Ab group, the proportion of PD in patients with Amp11q13 and nonAmp11q13 had no significant difference (0% vs 11.1%, P>0.99). In the PD-1Ab group, the median progression-free survival (PFS) was 1.5 months in Amp11q13 patients vs 16.2 months in non-Amp11q13 patients (HR, 0.05; 95% CI 0.01-0.45; P = 0.0003). No significant difference was observed in the nonPD-1Ab group. Notably, we found that hyperprogressive disease (HPD) might be associated with Amp11q13. The increased density of Foxp3+ Treg cells in HCC patients with Amp11q13 might be one of potential mechanisms. Conclusion: HCC patients with Amp11q13 are less likely to benefit from PD-1 blockade therapies. These findings may help guide the use of immunotherapy for HCC in routine clinical practice.

A prediction model for new-onset atrial fibrillation following coronary artery bypass graft surgery: A multicenter retrospective study.

Objective: Developing and assessing a risk prediction model of postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG), and aims to provide a reference for the prediction and prevention. Design: A retrospective case-control study. Setting: Three major urban teaching and university hospitals and tertiary referral centers. Participants: consecutive patients undergoing CABG. Interventions: The study was retrospective and no interventions were administered to patients. Measurements and main results: In the study, the overall new-onset POAF prevalence was approximately 28%. A prediction model for POAF with nine significant indicators was developed, and identified new predictors of POAF: left ventricular end diastolic diameter (LVEDD), intraoperative defibrillation, and intraoperative temporary pacing lead implantation. The model had good discrimination in both the derivation and validation cohorts, with the area under the receiver operating characteristic curves (AUCs) of 0.621 (95% CI = 0.602-0.640) and 0.616 (95% CI = 0.579-0.651), respectively, and showed good calibration. Compared with CHA2DS2-VASc, HATCH score, and the prediction model of POAF after CABG developed based on a small sample of clinical data from a single center in China, the model in this study had better discrimination. Conclusion: We have developed and validated a new prediction model of POAF after CABG using multicenter data that can be used in the clinic for early identification of high-risk patients of POAF, and to help effectively prevent POAF in postoperative patients.