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1.
Article in English | MEDLINE | ID: mdl-38696218

ABSTRACT

The newly emerging liquid metal flexible electronics are gaining increasing applications over the world due to their outstanding adaptability and printability. Here, we proposed a generalized purpose thermo-activated hybrid transfer printing method for the rapid fabrication of multifunctional soft electronics, which can significantly reduce the difficulty facing existing technologies. This printing involves two delivery and deposition processes of liquid metals and the allied inks (toners) based on their adhesion selection mechanisms. Through developing office supplies, the laser printer could directly print toner masks on soft substrates, such as polydimethylsiloxane film. The heating plate was applied to remove the toner sacrificial mask after rolling liquid metal inks, resulting in retaining the liquid metal circuits on the target substrate. For illustration, diverse materials and inks are adapted to the strategy of constructing flexible electronics. Particularly, colorful circuits, flexible heaters, transparent circuitry, and soft programmable light-emitting diode array displays with multilayer circuits have been fabricated and tested. This general and easily accessible method allows for the rapid acquisition of user-designed soft electronics and is expected to promote the widespread use of flexible electronics in e-skin, sensing, displays, etc.

2.
Bioinspir Biomim ; 2024 May 09.
Article in English | MEDLINE | ID: mdl-38722361

ABSTRACT

Aiming at the blade flutter of large horizontal-axis wind turbines, a method by utilizing biomimetic corrugation to suppress blade flutter is first proposed. By extracting the dragonfly wing corrugation, the biomimetic corrugation airfoil is constructed, finding that mapping corrugation to the airfoil pressure side has better aerodynamic performance. The influence of corrugation type, amplitude λ, and intensity on airfoil flutter is analyzed using orthogonal experiment, which determines that the λ has the greatest influence on airfoil flutter. Based on the drag coefficient flutter index δ, the optimal airfoil flutter suppression effect is obtained when the type is III, λ=0.6, and intensity is denser (n=13). The effective corrugation layout area in the chord direction is determined to be the leading edge, and the δ of corrugation airfoil is reduced by 5.049%, compared to the original airfoil. The application of this corrugation to NREL 15 MW wind turbine 3D blades is studied, and the influence of corrugation layout length in the blade span direction on the suppressive effect is analyzed by fluid-structure interaction. It is found that when the layout length is 0.85R, the safety margin Sf reaches a maximum value of 0.3431 Hz, which is increased 2.940%. The results show that the biomimetic corrugated structure proposed in this paper can not only improve the aerodynamic performance by changing the local flow field on the surface of the blade, but also increase the structural stiffness of the blade itself, and achieve the effect of flutter suppression.

3.
BMC Vet Res ; 20(1): 182, 2024 May 08.
Article in English | MEDLINE | ID: mdl-38720329

ABSTRACT

BACKGROUND: Porcine cysticercosis, a serious zoonotic parasitic disease, is caused by the larvae of Taenia solium and has been acknowledged by the World Organization for Animal Health. The current detection methods of Cysticercus cellulosae cannot meet the needs of large-scale and rapid detection in the field. We hypothesized that the immunofluorescence chromatography test strip (ICS) for detecting Cysticercus cellulosae, according to optimization of a series of reaction systems was conducted, and sensitivity, specificity, and stability testing, and was finally compared with ELISA. This method utilizes Eu3+-labeled time-resolved fluorescent microspheres (TRFM) coupled with TSOL18 antigen to detect TSOL18 antibodies in infected pig sera. RESULTS: ICS and autopsy have highly consistent diagnostic results (n = 133), as determined by Cohen's κ analysis (κ = 0.925). And the results showed that the proposed ICS are high sensitivity (0.9459) with specificity (0.9792). The ICS was unable to detect positive samples of other parasites. It can be stored for at least six months at 4℃. CONCLUSIONS: In summary, we established a TRFM-ICS method with higher sensitivity and specificity than indirect ELISA. Results obtained from serum samples can be read within 10 min, indicating a rapid, user-friendly test suitable for large-scale field detection.


Subject(s)
Antibodies, Helminth , Antigens, Helminth , Cysticercosis , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique , Sensitivity and Specificity , Swine Diseases , Animals , Swine , Swine Diseases/diagnosis , Swine Diseases/parasitology , Swine Diseases/blood , Cysticercosis/veterinary , Cysticercosis/diagnosis , Antibodies, Helminth/blood , Antigens, Helminth/blood , Antigens, Helminth/immunology , Fluorescent Antibody Technique/veterinary , Fluorescent Antibody Technique/methods , Enzyme-Linked Immunosorbent Assay/veterinary , Enzyme-Linked Immunosorbent Assay/methods , Cysticercus/immunology , Taenia solium/immunology
4.
Int J Biol Macromol ; 269(Pt 2): 132128, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38723807

ABSTRACT

Selenium-rich tea polysaccharides (Se-TPS) were extracted via high hydrostatic pressure technology with a pressure of 400 MPa (200-500 MPa) for 10 min (3-20 min) at a material-to-solvent ratio of 1:40 (1:20-1:50). Subsequently, Se-TPS1-4 were isolated and purified, with Se-TPS3-4 as the main components. A spectral analysis proved that Se, which has antioxidant activity, existed. An in vitro study found that among Se-TPS, Se-TPS3-4 attenuated the release of ß-hexosaminidase, histamine, and interleukin (IL)-4. Furthermore, in vivo experiments revealed that treatment with Se-TPS downregulated IL-4 levels and upregulated TGF-ß and interferon-γ levels to improve imbalanced Th1/Th2 immunity in tropomyosin-sensitized mice. Moreover, Se-TPS promoted Lactobacillus and norank_f_Muribaculaceaek growth and upregulated metabolites such as genipin and coniferyl alcohol. Overall, these results showed the strong anti-allergy potential of Se-TPS by regulating mast cell-mediated allergic inflammatory responses and microbiota regulation, highlighting the potential of Se-TPS as a novel therapeutic agent to regulate allergy-associated metabolic disorders.

5.
Front Cell Infect Microbiol ; 14: 1384284, 2024.
Article in English | MEDLINE | ID: mdl-38725451

ABSTRACT

Japanese spotted fever (JSF) is caused by Rickettsia japonica, mainly vectored by hard ticks. However, whether R. japonica can be transmitted by other arthropods remains unknown. Moreover, it is of interest to investigate whether other Rickettsia species cause spotted fever in endemic areas. In this study, a survey of Rickettsia species was performed in hematophagous arthropods (mosquitoes, tabanids, and ticks) from endemic areas for JSF in Hubei Province, central China. The results showed that the diversity and prevalence of Rickettsia species in mosquitoes are low, suggesting that mosquitoes may not be the vector of zoonotic Rickettsia species. A novel Rickettsia species showed a high prevalence (16.31%, 23/141) in tabanids and was named "Candidatus Rickettsia tabanidii." It is closely related to Rickettsia from fleas and mosquitoes; however, its pathogenicity in humans needs further investigation. Five Rickettsia species were identified in ticks. Rickettsia japonica, the agent of JSF, was detected only in Haemaphysalis longicornis and Haemaphysalis hystricis, suggesting that they may be the major vectors of R. japonica. Notably, two novel species were identified in H. hystricis ticks, one belonging to the spotted fever group and the other potentially belonging to the ancestral group. The latter one named "Candidatus Rickettsia hubeiensis" may provide valuable insight into the evolutionary history of Rickettsia.


Subject(s)
Phylogeny , Rickettsia , Spotted Fever Group Rickettsiosis , Animals , Rickettsia/isolation & purification , Rickettsia/genetics , Rickettsia/classification , China/epidemiology , Spotted Fever Group Rickettsiosis/microbiology , Spotted Fever Group Rickettsiosis/epidemiology , Ticks/microbiology , Humans , Arthropods/microbiology , DNA, Bacterial/genetics , Culicidae/microbiology , RNA, Ribosomal, 16S/genetics , Endemic Diseases , Sequence Analysis, DNA , Siphonaptera/microbiology
6.
Ther Adv Chronic Dis ; 15: 20406223241247648, 2024.
Article in English | MEDLINE | ID: mdl-38726235

ABSTRACT

In 2020, the European Medicines Agency approved subcutaneous (SC) vedolizumab (VDZ) for the maintenance treatment of adult patients with moderate to severe inflammatory bowel disease (IBD). This article reviews the efficacy, safety, persistence, pharmacology, patient satisfaction, and economic implications of transitioning to SC VDZ treatment and explores whether SC formulations can be recommended by the same guidelines as intravenous (IV) formulations. Clinical trials and real-world evidence indicate that transitioning from IV to SC VDZ in patients with IBD maintains clinical, biochemical, and patient-reported clinical remission and is well-tolerated, with no new safety issues identified, except for injection site reactions. Moreover, SC VDZ has an exposure-response relationship and low immunogenicity, is economical, and provides a high level of patient satisfaction. Owing to these advantages, transitioning may be advisable. In the future, more studies are needed to clarify the exact role of SC VDZ in IBD treatment, including optimization and transitioning strategies and individualized treatments based on baseline characteristics.


Subcutaneous vedolizumab for inflammatory bowel disease Transitioning from intravenous to subcutaneous vedolizumab (SC VDZ) in patients with inflammatory bowel disease maintains clinical, biochemical, and patient-reported clinical remission and is well-tolerated, with no new safety issues identified, except for injection site reactions. Moreover, SC VDZ has an exposure-response relationship and low immunogenicity, is economical, and provides a high level of patient satisfaction. Owing to these advantages, transitioning may be advisable.

7.
Am J Cancer Res ; 14(4): 1850-1865, 2024.
Article in English | MEDLINE | ID: mdl-38726266

ABSTRACT

Chronic inflammation associated with lung cancers contributes to immunosuppressive tumor microenvironments, reducing CD8+ T-cell function and leading to poor patient outcomes. A disintegrin and metalloprotease domain 9 (ADAM9) promotes cancer progression. Here, we aim to elucidate the role of ADAM9 in the immunosuppressive tumor microenvironment. A bioinformatic analysis of TIMER2.0 was used to investigate the correlation of ADAM9 and to infiltrate immune cells in the human lung cancer database and mouse lung tumor samples. Flow cytometry, immunohistochemistry, and RNA sequencing (RNA-seq) were performed to investigate the ADAM9-mediated immunosuppressive microenvironment. The coculture system of lung cancer cells with immune cells, cytokine array assays, and proteomic approach was used to investigate the mechanism. By analyzing the human LUAD database and the mouse lung cancer models, we showed that ADAM9 was associated with the immunosuppressive microenvironment. Additionally, ADAM9 released IL6 protein from cancer cells to inhibit IL12p40 secretion from dendritic cells, therefore leading to dendritic cell dysfunction and further affecting T-cell functions. Proteomic analysis indicated that ADAM9 promoted cholesterol biosynthesis and increased IL6-STAT3 signaling. Mechanistically, ADAM9 reduced the protein stability of LDLR, resulting in reduced cholesterol uptake and induced cholesterol biosynthesis. Moreover, LDLR reduction enhanced IL6-STAT3 activation. We reveal that ADAM9 has a novel biological function that drives the immunosuppressive tumor microenvironment by linking lung cancer's metabolic and signaling axes. Thus, by targeting ADAM9 an innovative and promising therapeutic opportunity was indicated for regulating the immunosuppression of lung cancer.

9.
Adv Sci (Weinh) ; : e2309907, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38696589

ABSTRACT

Myocardial ischemia/reperfusion injury (MIRI) is the leading cause of irreversible myocardial damage. A pivotal pathogenic factor is ischemia/reperfusion (I/R)-induced cardiomyocyte ferroptosis, marked by iron overload and lipid peroxidation. However, the impact of lipid droplet (LD) changes on I/R-induced cardiomyocyte ferroptosis is unclear. In this study, an aggregation-induced emission probe, TPABTBP is developed that is used for imaging dynamic changes in LD during myocardial I/R-induced ferroptosis. TPABTBP exhibits excellent LD-specificity, superior capability for monitoring lipophagy, and remarkable photostability. Molecular dynamics (MD) simulation and super-resolution fluorescence imaging demonstrate that the TPABTBP is specifically localized to the phospholipid monolayer membrane of LDs. Imaging LDs in cardiomyocytes and myocardial tissue in model mice with MIRI reveals that the LD accumulation level increase in the early reperfusion stage (0-9 h) but decrease in the late reperfusion stage (>24 h) via lipophagy. The inhibition of LD breakdown significantly reduces the lipid peroxidation level in cardiomyocytes. Furthermore, it is demonstrated that chloroquine (CQ), an FDA-approved autophagy modulator, can inhibit ferroptosis, thereby attenuating MIRI in mice. This study describes the dynamic changes in LD during myocardial ischemia injury and suggests a potential therapeutic target for early MIRI intervention.

10.
Article in English | MEDLINE | ID: mdl-38733533

ABSTRACT

BACKGROUND: Advancements in nasopharyngeal carcinoma (NPC) treatment have led to a focus on personalized treatment. Circulating tumor cells (CTCs) are important for liquid biopsies and personalized treatment but are not being fully utilized. This study examined how pre- and post-treatment CTC counts, EMT subtypes, clinical characteristics, and patient prognosis are related in order to support the use of liquid biopsy in managing NPC. METHODS: This retrospective study included 141 patients with locally advanced NPC. All patients underwent CanPatrol™ CTC detection pre- and post-treatment and were categorized into EMT subtypes: epithelial type, mixed type, and mesenchymal type. This study analyzed CTC enumeration, EMT subtypes, and their associations with clinical characteristics and survival outcomes. RESULTS: The results indicated a positive correlation between the pre-treatment detection rate of CTCs and N stage (P < 0.01), alongside a positive correlation with the TNM clinical stage (P = 0.02). Additionally, the detection rate of mesenchymal CTCs post-treatment is positively associated with the N stage (P = 0.02). The enumeration of CTCs pre- and post-treatment is negatively correlated with prognosis and has statistical significance. Additionally, an investigation into the EMT subtypes of CTCs revealed a significant association between the presence of mesenchymal CTCs pre- and post-treatment and decreased overall survival (OS) (P < 0.05). Furthermore, T stage, N stage, TNM clinical stage, and Epstein-Barr virus (EBV) DNA were also significantly correlated with OS. CONCLUSION: The study found that mesenchymal CTCs pre- and post-treatment, as well as the number of CTCs, were linked to a poor prognosis.

11.
Food Chem ; 452: 139355, 2024 Apr 13.
Article in English | MEDLINE | ID: mdl-38733679

ABSTRACT

Differently colored foxtail millet (Setaria italica) cultivars were compared regarding their amylose, B-complex vitamin, vitamin E, and phenolic compositions, as well as the bioaccessibility of their phenolics in simulated in vitro digestion. Dark-colored foxtail millets contained more thiamine, pyridoxine, and tocopherols, but less riboflavin, than light-colored ones. Phenolics were more abundant in dark-colored cultivars. Insoluble bound fractions accounted for 75%-83% of the total phenolics, with ferulic acid detected as the most plentiful compound. The major bioaccessible phenolic was free ferulic acid, with 100%-120% bioaccessibility, depending on cultivar, followed by p-coumaric acid and isoferulic acid (50%-80%). These relatively high bioaccessibilities were likely due to the release of soluble conjugated or insoluble bound phenolics during digestion. However, the contents of other free phenolics were largely decreased following in vitro digestion, resulting in low bioaccessibility, which also means that the release from the conjugated and bound fractions was poor.

12.
Toxicol Lett ; 2024 May 09.
Article in English | MEDLINE | ID: mdl-38734218

ABSTRACT

Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5µM). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.

13.
Mol Biol Rep ; 51(1): 650, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38734811

ABSTRACT

BACKGROUND: Vitiligo is a common autoimmune skin disease. Capsaicin has been found to exert a positive effect on vitiligo treatment, and mesenchymal stem cells (MSCs) are also confirmed to be an ideal cell type. This study aimed to explore the influence of capsaicin combined with stem cells on the treatment of vitiligo and to confirm the molecular mechanism of capsaicin combined with stem cells in treating vitiligo. METHODS AND RESULTS: PIG3V cell proliferation and apoptosis were detected using CCK-8 and TUNEL assays, MitoSOX Red fluorescence staining was used to measure the mitochondrial ROS level, and JC-1 staining was used to detect the mitochondrial membrane potential. The expression of related genes and proteins was detected using RT‒qPCR and Western blotting. Coimmunoprecipitation was used to analyze the protein interactions between HSP70 and TLR4 or between TLR4 and mTOR. The results showed higher expression of HSP70 in PIG3V cells than in PIG1 cells. The overexpression of HSP70 reduced the proliferation of PIG3V cells, promoted apoptosis, and aggravated mitochondrial dysfunction and autophagy abnormalities. The expression of HSP70 could be inhibited by capsaicin combined with MSCs, which increased the levels of Tyr, Tyrp1 and DCT, promoted the proliferation of PIG3V cells, inhibited apoptosis, activated autophagy, and improved mitochondrial dysfunction. In addition, capsaicin combined with MSCs regulated the expression of TLR4 through HSP70 and subsequently affected the mTOR/FAK signaling pathway CONCLUSIONS: Capsaicin combined with MSCs inhibits TLR4 through HSP70, and the mTOR/FAK signaling pathway is inhibited to alleviate mitochondrial dysfunction and autophagy abnormalities in PIG3V cells.


Subject(s)
Apoptosis , Capsaicin , Cell Proliferation , HSP70 Heat-Shock Proteins , Melanocytes , Mitochondria , Signal Transduction , TOR Serine-Threonine Kinases , Toll-Like Receptor 4 , Vitiligo , Toll-Like Receptor 4/metabolism , Humans , Mitochondria/metabolism , Mitochondria/drug effects , Signal Transduction/drug effects , HSP70 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/genetics , TOR Serine-Threonine Kinases/metabolism , Vitiligo/metabolism , Vitiligo/drug therapy , Capsaicin/pharmacology , Cell Proliferation/drug effects , Apoptosis/drug effects , Melanocytes/metabolism , Melanocytes/drug effects , Cell Line , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/drug effects , Membrane Potential, Mitochondrial/drug effects , Autophagy/drug effects
14.
Article in English | MEDLINE | ID: mdl-38712770

ABSTRACT

Objective: Studies have demonstrated that tonsillectomy may alter the risk of oropharyngeal cancer (OPC). We systematically reviewed the evidence and pooled data to examine such an association. Methods: PubMed, Embase, and Scopus were searched up to 25th April 2023. Studies reporting an association between tonsillectomy and oropharyngeal cancer risk at any site were included. Results: Five studies were eligible. All examined the risk of tonsillar and base of the tongue (BOT) cancer with prior history of tonsillectomy. On meta-analysis of the data, prior history of tonsillectomy was associated with a significantly decreased risk of tonsillar cancer. The second meta-analysis showed that history of tonsillectomy did not significantly alter the risk of BOT cancer. However, after exclusion of one study, the results showed an increased risk of BOT cancer with a history of tonsillectomy. Conclusions: The scarce data available in the literature suggests that tonsillectomy may reduce the risk of tonsillar cancer but does not alter the risk of BOT cancer. Further studies are needed to explore the association between tonsillectomy and the risk of OPC.

15.
Cell Transplant ; 33: 9636897241244943, 2024.
Article in English | MEDLINE | ID: mdl-38695366

ABSTRACT

Multipotent mesenchymal stem cells (MSCs) have high self-renewal and multi-lineage differentiation potentials and low immunogenicity, so they have attracted much attention in the field of regenerative medicine and have a promising clinical application. MSCs originate from the mesoderm and can differentiate not only into osteoblasts, cartilage, adipocytes, and muscle cells but also into ectodermal and endodermal cell lineages across embryonic layers. To design cell therapy for replacement of damaged tissues, it is essential to understand the signaling pathways, which have a major impact on MSC differentiation, as this will help to integrate the signaling inputs to initiate a specific lineage. Hedgehog (Hh) signaling plays a vital role in the development of various tissues and organs in the embryo. As a morphogen, Hh not only regulates the survival and proliferation of tissue progenitor and stem populations but also is a critical moderator of MSC differentiation, involving tri-lineage and across embryonic layer differentiation of MSCs. This review summarizes the role of Hh signaling pathway in the differentiation of MSCs to mesodermal, endodermal, and ectodermal cells.


Subject(s)
Cell Differentiation , Hedgehog Proteins , Mesenchymal Stem Cells , Signal Transduction , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Hedgehog Proteins/metabolism , Humans , Cell Differentiation/physiology , Animals , Multipotent Stem Cells/cytology , Multipotent Stem Cells/metabolism
16.
Ultrason Sonochem ; 106: 106883, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38703594

ABSTRACT

Ultrasound has been widely used in industry due to its high energy and efficiency. This study optimized the ultrasonic-assisted extraction (UAE) process of frosted figs pectin (FFP) using response surface methodology (RSM), and further investigated the effect of ultrasonic power on the structural characteristics and antioxidant activities of FFPs. The UAE method of FFP through RSM was optimized, and the optimal extraction process conditions, particle size of 100 mesh, pH value of 1.95, liquid-solid ratio of 47:1 (mL/g), extraction temperature of 50 °C and extraction time of 65 min, were obtained. The extraction rate of FFP under this condition was 37.97 ± 2.56 %. Then, the four FFPs modified by ultrasound were obtained by changing the ultrasonic power. Research had found that ultrasonic power had little effect on the monosaccharide composition, Zeta potential, as well as the thermal stability and appearance structure of the four FFPs. However, ultrasonic power had a significant impact on other properties of FFP: as the ultrasonic power increased, the DM% and particle size decreased continuously, while the total carbohydrate content increased. Meanwhile, ultrasonic power also had a significant impact on antioxidant activities of FFPs. From the research results, it could be seen that different ultrasonic power had certain changes in its spatial structure and properties, and the structural changes also affected the biological activity of FFP. The study of the effects of ultrasonic power on the physicochemical properties and biological activity of FFP lays the foundation for the development and application of FFP in food additives and natural drug carriers.

17.
Adv Mater ; : e2404330, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38723269

ABSTRACT

The pursuit of constructing humanoid robots to replicate the anatomical structures and capabilities of human beings has been a long-standing significant undertaking and especially garnered tremendous attention in recent years. However, despite the progress made over recent decades, humanoid robots have predominantly been confined to those rigid metallic structures, which however starkly contrast with the inherent flexibility observed in biological systems. To better innovate this area, the present article systematically explores the value and potential of liquid metals and their derivatives in facilitating a crucial transition towards soft humanoid robots. Through a comprehensive interpretation of bionics, we present an overview of liquid metals' multifaceted roles as essential components in constructing advanced humanoid robots - functioning as soft actuators, sensors, power sources, logical devices, circuit systems, and even transformable skeletal structures. We conceived that the integration of these components with flexible structures, facilitated by the unique properties of liquid metals, can create unexpected versatile functionalities and behaviors to better fulfill human needs. Finally, we envision a revolution in humanoid robots, transitioning from metallic frameworks to hybrid soft-rigid structures resembling that of biological tissues. This article is expected to provide fundamental guidance for the coming research, thereby advancing the area. This article is protected by copyright. All rights reserved.

18.
Cancer Res ; 2024 May 08.
Article in English | MEDLINE | ID: mdl-38718296

ABSTRACT

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Here, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments.

19.
Cell Death Differ ; 2024 May 08.
Article in English | MEDLINE | ID: mdl-38719928

ABSTRACT

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

20.
Arch Acad Emerg Med ; 12(1): e31, 2024.
Article in English | MEDLINE | ID: mdl-38721446

ABSTRACT

Introduction: Aneurysmal subarachnoid hemorrhage (SAH) constitutes a life-threatening condition, and identifying the ruptured aneurysm is essential for further therapy. This study aimed to evaluate the diagnostic accuracy of hypo-attenuating berry sign (HBS) observed on computed tomography (CT) scan in distinguishing ruptured aneurysms. Methods: In this diagnostic accuracy study, patients who had SAH and underwent non-enhanced brain CT scan were recruited. The HBS was defined as a hypo-attenuating area with an identifiable border in the blood-filled hyper-dense subarachnoid space. The screening performance characteristics of HBS in identifying ruptured aneurysms were calculated considering the digital subtraction angiography (DSA) as the gold standard. Results: A total of 129 aneurysms in 131 patients were analyzed. The overall sensitivity and specificity of HBS in the diagnosis of aneurysms were determined to be 78.7% (95%CI: 73.1% - 83.4%) and 70.7% (95%CI: 54.3% - 83.4%), respectively. Notably, the sensitivity increased to 90.9% (95%CI: 84.3% - 95.0%) for aneurysms larger than 5mm. The level of inter-observer agreement for assessing the presence of HBS was found to be substantial (kappa=0.734). The diagnostic accuracy of HBS in individuals exhibited enhanced specificity, sensitivity, and reliability when evaluating patients with a solitary aneurysm or assessing ruptured aneurysms. The multivariate logistic regression analysis revealed a statistically significant relationship between aneurysm size and the presence of HBS (odds ratios of 1.667 (95%CI: 1.238 - 2.244; p < 0.001) and 1.696 (95%CI: 1.231 - 2.335; p = 0.001) for reader 1 and reader 2, respectively). Conclusions: The HBS can serve as a simple and easy-to-use indicator for identifying a ruptured aneurysm and estimating its size in SAH patients.  .

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