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Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.
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Neoplasias , Receptor Toll-Like 7 , Animales , Ratones , Receptor Toll-Like 7/agonistas , Especies Reactivas de Oxígeno , Inmunoterapia/métodos , Neoplasias/terapia , Adyuvantes Inmunológicos , Polímeros/química , Vacunación , Línea Celular TumoralRESUMEN
Cancer immunotherapy harnesses the immune system to combat cancer, yet tumors often evade immune surveillance through immunosuppressive cells. Herein, we report an organic semiconducting sono-metallo-detonated immunobomb (SMIB) to spatiotemporally tame immunosuppressive cells in situ. SMIB consists of an amphiphilic semiconducting polymer (SP) with a repeatable thiophene-based Schiff base serving as an iron ion chelator (Fe3+). SMIB increases sonochemical activity through iron chelation and reduces immunosuppressive cell differentiation with metals and sonochemicals, thereby decreasing the irradiation dose. Upon ultrasound irradiation, SMIB acts as a sono-metallo-detonated immunobomb and inhibits Tregs via the mTOR pathway and M2 macrophage polarization through GPX4 regulation. Ultrasensitized sono-generated reactive oxygen species also promote activation of antigen-presenting cells in deep solid tumors (1 cm), resulting in cytotoxic T cell infiltration and enhanced antitumor efficacy. This platform provides a versatile approach for synergistic sono- and metalloregulation of immunosuppressive cells in situ.
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To elucidate the induction of ferroptotic pathways and the transcriptional modulation of pivotal genes in the context of hemorrhagic shock. The R software was used to analyze the GSE64711 dataset, isolating genes relevant to ferroptosis. Enrichment analyses and protein interaction networks were assembled. Using WGCNA hub genes were identified and intersected with ferroptosis-related genes, highlighting hub genes CD44 and MAPK14. In a rat hemorrhagic shock model, cardiac ROS, Fe2+, MDA, and GSH levels were assessed. Key ferroptotic proteins (SLC7A11/GPX4) in myocardial tissues were examined via western blot. Hub genes, CD44 and MAPK14, expressions were confirmed through immunohistochemistry. Analyzing the GSE64711 dataset revealed 337 differentially expressed genes, including 12 linked to ferroptosis. Enrichment analysis highlighted pathways closely related to ferroptosis. Using Genemania, we found these genes mainly affect ROS metabolism and oxidative stress response. WGCNA identified CD44 and MAPK14 as hub genes. Rat myocardial tissue validation showed significant cardiac damage and elevated ROS and MDA levels, and decreased GSH levels in the hemorrhagic shock model. The ferroptotic pathway SLC7A11/GPX4 was activated, and immunohistochemistry showed a significant increase in the expression levels of CD44 and MAPK14 in the hemorrhagic shock rat model. We demonstrated the presence of tissue ferroptosis in hemorrhagic shock by combining bioinformatics analysis with in vivo experimentation. Specifically, we observed the activation of the SLC7A11/GPX4 ferroptotic pathway. Further, CD44 and MAPK14 were identified as hub genes in hemorrhagic shock.
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Ferroptosis , Proteína Quinasa 14 Activada por Mitógenos , Choque Hemorrágico , Animales , Ratas , Ferroptosis/genética , Especies Reactivas de Oxígeno , Choque Hemorrágico/genética , ApoptosisRESUMEN
OBJECTIVE: Sepsis and sepsis-associated organ failure are devastating conditions for which there are no effective therapeutic agent. Several studies have demonstrated the significance of ferroptosis in sepsis. The study aimed to identify ferroptosis-related genes (FRGs) in sepsis, providing potential therapeutic targets. METHODS: The weighted gene co-expression network analysis (WGCNA) was utilized to screen sepsis-associated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to explore gene functions. Three machine learning methods were employed to identify sepsis-related hub genes. Survival and multivariate Cox regression analysis allowed further screening for the key gene RRM2 associated with prognosis. The immune infiltration analysis of the screened sepsis key genes was performed. Additionally, a cecum ligation and puncture (CLP)-induced mouse sepsis model was constructed to validate the expression of key gene in the sepsis. RESULTS: Six sepsis-associated differentially expressed FRGs (RRM2, RPL7A, HNRNPA1, PEBP1, MYL8B and TXNIP) were screened by WGCNA and three machine learning methods analysis. Survival analysis and multivariate Cox regression analysis showed that RRM2 was a key gene in sepsis and an independent prognostic factor associated with clinicopathological and molecular features of sepsis. Immune cell infiltration analysis demonstrated that RRM2 had a connection to various immune cells, such as CD4 T cells and neutrophils. Furthermore, animal experiment demonstrated that RRM2 was highly expressed in CLP-induced septic mice, and the use of Fer-1 significantly inhibited RRM2 expression, inhibited serum inflammatory factor TNF-α, IL-6 and IL-1ß expression, ameliorated intestinal injury and improved survival in septic mice. CONCLUSION: RRM2 plays an important role in sepsis and may contribute to sepsis through the ferroptosis pathway. This study provides potential therapeutic targets for sepsis.
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Ferroptosis , Ribonucleósido Difosfato Reductasa , Sepsis , Animales , Ratones , Linfocitos T CD4-Positivos , Ciego , Modelos Animales de Enfermedad , Ferroptosis/genética , Sepsis/genética , Factor de Necrosis Tumoral alfa , Ribonucleósido Difosfato Reductasa/metabolismoRESUMEN
Eosinophils are important immune effector cells that affect Tâ cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2-cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and Tâ cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.
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Eosinófilos , Inmunoterapia , Nanopartículas , Polímeros , Nanopartículas/química , Polímeros/química , Polímeros/farmacología , Ratones , Animales , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Eosinófilos/inmunología , Semiconductores , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/patología , Fotoquimioterapia , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
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Nanopartículas , Neoplasias , Aloinjertos , Detección Precoz del Cáncer , Humanos , RiñónRESUMEN
INTRODUCTION: Inflammation is a defensive response of the organism to irritation which is manifested by redness, swelling, heat, pain and dysfunction. The inflammatory response underlies the role of various diseases. Ferroptosis, a unique modality of cell death, driven by iron-dependent lipid peroxidation, is regulated by multifarious cellular metabolic pathways, including redox homeostasis, iron processing and metabolism of lipids, as well as various signaling pathways associated with diseases. A growing body of evidence suggests that ferroptosis is involved in inflammatory response, and targeting ferroptosis has great prospects in preventing and treating inflammatory diseases. MATERIALS AND METHODS: Relevant literatures on ferroptosis, inflammation, inflammatory factors and inflammatory diseases published from January 1, 2010 to now were searched in PubMed database. CONCLUSION: In this review, we summarize the regulatory mechanisms associated with ferroptosis, discuss the interaction between ferroptosis and inflammation, the role of mitochondria in inflammatory ferroptosis, and the role of targeting ferroptosis in inflammatory diseases. As more and more studies have confirmed the relationship between ferroptosis and inflammation in a wide range of organ damage and degeneration, drug induction and inhibition of ferroptosis has great potential in the treatment of immune and inflammatory diseases.
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Ferroptosis , Humanos , Inflamación , Muerte Celular , Homeostasis , Hierro , Peroxidación de LípidoRESUMEN
OBJECTIVE: Bronchopulmonary dysplasia is a chronic lung disease in premature infants with alveolar simplification and pulmonary vascular development disorder as the main pathological feature and hyperoxia as the main etiology. Autophagy is a highly conserved cytological behavior of self-degrading cellular components and is accompanied by oxidative stress. Studies have reported that autophagy is regulated by FOXO1 posttranslational modification. However, whether autophagy can be involved in the regulation of endothelial cell injury induced by hyperoxia and its mechanism are still unclear. STUDY DESIGN: We have activated and inhibited autophagy in human umbilical vein endothelial cells under hyperoxia and verified the role of autophagy in endothelial cell-related functions from both positive and negative aspects. RESULTS: Our research showed that the expression level of autophagy-related proteins decreased, accompanied by decreased cell migration ability and tube formation ability and increased cell reactive oxygen species level and cell permeability under hyperoxia conditions. Using an autophagy agonist alleviated hyperoxia-induced changes and played a protective role. However, inhibition of autophagy aggravated the cell damage induced by hyperoxia. Moreover, the decrease in autophagy proteins was accompanied by the upregulation of FOXO1 phosphorylation and acetylation. CONCLUSION: We concluded that autophagy was a protective mechanism against endothelial cell injury caused by hyperoxia. Autophagy might participate in this process by coregulating posttranslational modifications of FOXO1. KEY POINTS: · Hyperoxia induces vascular endothelial cell injury.. · Autophagy may has a protective role under hyperoxia conditions.. · FOXO1 posttranslational modification may be involved in the regulation of autophagy..
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Brassinosteroids (BRs) play pivotal roles in improving plant stress tolerance. To investigate the mechanism of BR regulation of salt tolerance in kiwifruit, we used 'Hongyang' kiwifruit as the test material. We exposed the plants to 150 mmol/L NaCl stress and irrigated them with exogenous BR (2,4-epibrassinolide). The phenotypic analysis showed that salt stress significantly inhibited photosynthesis in kiwifruit, leading to a significant increase in the H2O2 content of leaves and roots and a significant increase in Na+/K+, resulting in oxidative damage and an ion imbalance. BR treatment resulted in enhanced photosynthesis, reduced H2O2 content, and reduced Na+/K+ in leaves, alleviating the salt stress injury. Furthermore, transcriptome enrichment analysis showed that the differentially expressed genes (DEGs) related to BR treatment are involved in pathways such as starch and sucrose metabolism, pentose and glucuronate interconversions, and plant hormone signal transduction, among others. Among the DEGs involved in plant hormone signal transduction, those with the highest expression were involved in abscisic acid signal transduction. Moreover, there was a significant increase in the expression of the AcHKT1 gene, which regulates ion transduction, and the antioxidant enzyme AcFSD2 gene, which is a key gene for improving salt tolerance. The data suggest that BRs can improve salt tolerance by regulating ion homeostasis and reducing oxidative stress.
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Brasinoesteroides , Reguladores del Crecimiento de las Plantas , Brasinoesteroides/farmacología , Brasinoesteroides/metabolismo , Reguladores del Crecimiento de las Plantas/farmacología , Reguladores del Crecimiento de las Plantas/metabolismo , Peróxido de Hidrógeno/metabolismo , Perfilación de la Expresión Génica , Estrés Salino , Transcriptoma , Regulación de la Expresión Génica de las Plantas , Estrés FisiológicoRESUMEN
Chuanxiong rhizoma (CX) has been utilized for centuries as a traditional herb to treat blood stasis syndromes. However, the pharmacological mechanisms are still not completely revealed. This research was aimed at exploring the molecular mechanisms of CX treatment for thrombosis. Network pharmacology was used to predict the potential anti-thrombosis mechanism after correlating the targets of active components with targets of thrombosis. Furthermore, we verified the mechanism of using CX to treat thrombosis via molecular docking and in vitro experiments. Network pharmacology results showed that a total of 18 active ingredients and 65 targets of CX treatment for thrombosis were collected, including 8 core compounds and 6 core targets. We revealed for the first time that tissue factor (TF) had a close relationship with most core targets of CX in the treatment of thrombosis. TF is a primary coagulation factor in physiological hemostasis and pathological thrombosis. Furthermore, core components of CX have strong affinity for core targets and TF according to molecular docking analysis. The in vitro experiments indicated that Ligustilide (LIG), the representative component of CX, could inhibit TF procoagulant activity, TF mRNA and protein over-expression in a dose-dependent manner in EA.hy926 cells through the PI3K/Akt/NF-κB signaling pathway. This work demonstrated that hemostasis or blood coagulation was one of the important biological processes in the treatment of thrombosis with CX, and TF also might be a central target of CX when used for treating thrombosis. The inhibition of TF might be a novel mechanism of CX in the treatment of thrombosis.
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Farmacología en Red , Trombosis , Humanos , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas , Trombosis/tratamiento farmacológico , Coagulación SanguíneaRESUMEN
NETosis, the peculiar type of neutrophil death, plays important roles in pro-tumorigenic functions and inhibits cancer immunotherapy. Non-invasive real-time imaging is thus imperative for prognosis of cancer immunotherapy yet remains challenging. Herein, we report a Tandem-locked NETosis Reporterâ 1 (TNR1 ) that activates fluorescence signals only in the presence of both neutrophil elastase (NE) and cathepsin G (CTSG) for the specific imaging of NETosis. In the aspect of molecular design, the sequence of biomarker-specific tandem peptide blocks can largely affect the detection specificity towards NETosis. In live cell imaging, the tandem-locked design allows TNR1 to differentiate NETosis from neutrophil activation, while single-locked reporters fail to do so. The near-infrared signals from activated TNR1 in tumor from living mice were consistent with the intratumoral NETosis levels from histological results. Moreover, the near-infrared signals from activated TNR1 negatively correlated with tumor inhibition effect after immunotherapy, thereby providing prognosis for cancer immunotherapy. Thus, our study not only demonstrates the first sensitive optical reporter for noninvasive monitoring of NETosis levels and evaluation of cancer immunotherapeutic efficacy in tumor-bearing living mice, but also proposes a generic approach for tandem-locked probe design.
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Trampas Extracelulares , Neoplasias , Animales , Ratones , Trampas Extracelulares/fisiología , Neutrófilos/fisiología , Biomarcadores , Colorantes , Pronóstico , Inmunoterapia , Neoplasias/diagnóstico por imagen , Neoplasias/terapiaRESUMEN
Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer-based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer-specific inhibition of collagen-crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo-immunotherapy. SPNcb is self-assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (ß-aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)-cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumor-overexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis.
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Aminopropionitrilo , Neoplasias , Aminopropionitrilo/farmacología , Matriz Extracelular , Colágeno , Inmunoterapia , Neoplasias/patologíaRESUMEN
Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near-infrared fluorescence signals to report cell-mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros-based urinalysis discriminates allograft rejection against other non-alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.
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Trasplante de Riñón , Animales , Ratones , Riñón/patología , Biomarcadores/orina , Diagnóstico Precoz , Aloinjertos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/patología , Rechazo de Injerto/orina , Enfermedad AgudaRESUMEN
Sono-immunotherapy holds great potential for deep tumor inhibition; however, smart sono-therapeutic agents to simultaneously eliminate 'domestic' tumor cells and regulate the 'community' tumor immune microenvironment have rarely been developed. Herein, we report a spatiotemporally controllable semiconducting iron-chelated nano-metallomodulator (SINM) for hypersensitive sono-metallo-immunotherapy of cancer. SINM consists of a semiconducting polymer (SP) backbone chelating iron ions (Fe3+ ) with thiophene-based Schiff base structure, and a hydrophilic side chain. Upon accumulation in tumors after systemic administration, SINM specifically arouses ferroptosis and M1 macrophage polarization due to its response toward the tumor redox environment; meanwhile, the chelation of Fe3+ enhances the sono-sensitizing effect of SPs, leading to enhanced generation of reactive oxygen species for immunogenic cell death. Such combined sonodynamic metallo-immunotherapy of SINM efficiently ablates deep tumor and spatiotemporally regulates immunophenotypes.
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Quelantes del Hierro , Neoplasias , Humanos , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Factores Inmunológicos , Adyuvantes Inmunológicos , Neoplasias/tratamiento farmacológico , Inmunoterapia , Hierro , Línea Celular Tumoral , Microambiente TumoralRESUMEN
The efficacy of combination immunotherapy has been limited by tumor specificity and immune-related adverse events (irAEs). Herein, we report the development of polymeric STING pro-agonists (PSPA), whose sono-immunotherapeutic efficacy is activated by sono-irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA-2) via the GSH-activatable linkers. Under sono-irradiation, PSPA serves as a sonosensitizer to generate 1 O2 and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA-2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off-target side effects. The activation of the STING pathway elevates the interferon-ß level and synergizes with SDT to enhance the anti-tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono-immunotherapy.
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Glutatión , Neoplasias , Humanos , Muerte Celular Inmunogénica , Inmunoterapia , Polímeros , Microambiente Tumoral , Neoplasias/terapia , Línea Celular TumoralRESUMEN
OBJECTIVES: To investigate the impact of the environmental layout of the neonatal intensive care unit (NICU) on clinical outcomes and neurological development in very/extremely preterm infants. METHODS: A total of 304 very/extremely preterm infants admitted to Children's Hospital of Chongqing Medical University between January 2021 and June 2022 within 24 hours after birth were included in this retrospective cohort study. Based on different environmental layouts in the NICU, the infants were divided into two groups: centralized layout group (n=157) and decentralized layout group (n=147). The clinical outcomes and Test of Infant Motor Performance (TIMP) scores at corrected gestational age between 34 to 51+6 weeks were compared between the two groups. RESULTS: The decentralized layout group had lower incidence rates of bronchopulmonary dysplasia (44.9% vs 62.4%, P<0.05) and intracranial hemorrhage (17.7% vs 28.0%, P<0.05) than the centralized layout group. The cure rate was higher in the decentralized layout group compared to the centralized layout group (68.7% vs 56.7%, P<0.05). The decentralized layout group had higher TIMP scores than the centralized layout group at corrected gestational age between 34 to 51+6 weeks (P<0.05). CONCLUSIONS: The decentralized layout of the NICU exhibits positive effects on the clinical outcomes and early neurological development compared to the centralized layout in very/extremely preterm infants.
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Enfermedades del Prematuro , Unidades de Cuidado Intensivo Neonatal , Humanos , Recién Nacido , Recien Nacido Extremadamente Prematuro , Recién Nacido de muy Bajo Peso , Estudios RetrospectivosRESUMEN
Immunotherapy that stimulates the body's own immune system to kill cancer cells has emerged as a promising cancer therapeutic method. However, some types of cancer exhibited a low response rate to immunotherapy, and the high risk of immune-related side effects has been aroused during immunotherapy, which greatly restrict its broad applications in cancer therapy. Phototherapy that uses external light to trigger the therapeutic process holds advantages including high selectivity and efficiency, and low side effects. Recently, it has been proven to be able to stimulate immune response in the tumor region by inducing immunogenic cell death (ICD), the process of which was termed photo-immunotherapy, dramatically improving therapeutic specificity over conventional immunotherapy in several aspects. Among numerous optical materials for photo-immunotherapy, semiconducting polymer nanoparticles (SPNs) have gained more and more attention owing to their excellent optical properties and good biocompatibility. In this review, we summarize recent developments of SPNs for immunotherapy and imaging of immunoactivation. Different therapeutic modalities triggered by SPNs including photo-immunotherapy and photo-immunometabolic therapy are first introduced. Then, applications of SPNs for real-time monitoring immunoactivation are discussed. Finally, the conclusion and future perspectives of this research field are given.
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Nanopartículas , Neoplasias , Humanos , Inmunoterapia , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Fototerapia , Polímeros/uso terapéuticoRESUMEN
AIM: To investigate whether periodontitis impacts bone homeostasis via gut microbiota regulation. MATERIALS AND METHODS: Experimental periodontitis was induced by ligatures (LIG group). ApoE-/- mice were employed as a model with weakened bone homeostasis. Bone turnover was evaluated through micro-computerized tomography, haematoxylin and eosin-stained sections, osteoblast and osteoclast biomarkers in the bone and serum. Gut microbiota was analysed through 16S ribosomal RNA gene sequencing. Serum concentrations of cytokines were detected by enzyme-linked immunosorbent assay. The role of gut microbiota was evaluated through their transplantation into antibiotic-treated mice. RESULTS: Periodontitis significantly increased the number of osteoclasts and the expression of the osteoclast biomarkers in the proximal tibia of ApoE-/- mice, with the RANKL/OPG (receptor activator of nuclear factor-κB ligand/osteoprotegerin) ratio significantly increased, which indicated the osteoclastic activity overwhelmed osteogenesis. Meanwhile, periodontitis altered the composition of gut microbiota and induced low-grade inflammation in the colon and blood circulation. Interestingly, the concentration of circulating tumour necrosis factor-α, interleukin (IL)-6, IL-1ß, IL-17A, and monocyte chemotactic factor-1 were positively correlated with faecal α1-antitrypsin and calprotectin, as well as serum OPG and RANKL. Furthermore, transplantation of gut microbiota from mice with periodontitis to antibiotic-treated mice could partially re-capitulate the phenotypes in the bone and colon. CONCLUSION: Periodontitis may impair systemic bone homeostasis through gut microbiota.
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Pérdida de Hueso Alveolar , Microbioma Gastrointestinal , Periodontitis , Animales , Ratones , Antibacterianos/farmacología , Apolipoproteínas E/metabolismo , Biomarcadores/metabolismo , Homeostasis , Osteoclastos , Osteoprotegerina/metabolismo , Periodontitis/metabolismo , Ligando RANK/metabolismo , Ratones Noqueados para ApoERESUMEN
Sepsis-induced inflammatory response leads to intestinal damage and secondary bacterial translocation, causing systemic infections and eventually death. Emodin is a natural anthraquinone derivative in many plants with promising bioactivities. However, the effects and mechanisms of emodin on sepsis-induced intestinal dysfunctions have not been well clarified yet. We found that emodin treatment suppressed the inflammatory response in the intestines of septic mice. Intestinal barrier function was also improved by emodin through enhancing ZO-1 and occludin expression, which prevented the secondary translocation of Escherichia coli. By proteome microarray investigation, JNK2 was identified as a direct target of emodin. In vitro study also showed that emodin inhibited LPS-induced inflammatory response in intestinal epithelial cells. Nuclear factors including NF-κB and AP-1 were further identified as downstream effectors of JNK2. Bioinformatic analysis based on 16s rRNA gene sequencing illustrated that emodin treatment significantly increased the alpha- and beta-diversity of gut microbiota in septic mice. Moreover, data according to functional prediction showed that emodin decreased the abundance of potential pathogenic bacteria in gut. Our findings have shown that emodin treatment prevented inflammatory induced barrier dysfunction and decreased the potential pathogenicity of lumen bacteria, reducing the hazard of lumen bacterial translocation during sepsis.
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Emodina , Microbioma Gastrointestinal , Mucosa Intestinal , Sepsis , Animales , Emodina/uso terapéutico , Mucosa Intestinal/metabolismo , Lipopolisacáridos , Ratones , FN-kappa B/metabolismo , ARN Ribosómico 16S/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/microbiologíaRESUMEN
OBJECTIVE: The aim of this study was to investigate the diagnostic value of peripheral blood neutrophil-to-lymphocyte ratio (NLR) combined with the thyroid imaging reporting and data system (TIRADS) for benign and malignant thyroid nodules. METHODS: A total of 585 adults were enrolled in the study. The receiver operating characteristic curves were used to determine the optimal cut-off values for NLR and Kwak TIRADS (K-TIRADS) grades, which were 1.87 and 4a, respectively. Thyroid nodules were scored as follows: NLR-K-TIRADS score is 2 (both elevated K-TIRADS grade and NLR), NLR-K-TIRADS score is 1 (one of these was elevated) and NLR-k-TIRADS score is 0 (neither were elevated). RESULTS: The proportions of malignant nodules with NLR-K-TIRADS scores of 2, 1 and 0 were 98.59%, 69.62% and 10.19%, and the difference was statistically significant (p < 0.001). In terms of the sensitivity of diagnosis of malignant nodules, NLR-K-TIRADS 1 tends to increase relative to K-TIRADS grades ≥ 4a; in terms of specificity and positive predictive value for the diagnosis of malignant nodules, NLR-K-TIRADS 2 was significantly higher than K-TIRADS grades ≥ 4a (all p < 0.05). CONCLUSIONS: NLR combined with K-TIRADS grades may be a novel method for screening benign and malignant thyroid nodules.