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BACKGROUND: The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC. METHODS: This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ-2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance. RESULTS: Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance. CONCLUSIONS: These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Animais , Camundongos , Resistencia a Medicamentos Antineoplásicos , Feminino , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Linhagem Celular Tumoral , MutaçãoRESUMO
In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 µM) significantly enhanced the anti-tumor efficacy of osimertinib (1 µM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.
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Acrilamidas , Compostos de Anilina , Antineoplásicos , Receptor Tirosina Quinase Axl , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Camundongos Nus , Compostos Organofosforados , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas , Pirimidinas , Receptores Proteína Tirosina Quinases , Animais , Feminino , Camundongos , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Mutação , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this study, we designed and synthesized three conformation-adaptive Pd2L4- and Pd3L6-type coordination cages based on three dihydrophenazine-based ligands with different lengths. Interestingly, the shorter ligands L1 and L2 self-assembled into Pd2L4-type coordination cages while the longer ligand L3 formed Pd3L6-type one, mainly driven by the anion template effect. All coordination cages were confirmed through single-crystal X-ray diffraction, and their structural conformations underwent great changes compared with those of their corresponding ligands. Moreover, the conformational changes also significantly affected their photophysical and electrochemical properties which were distinct from their parent ligands.
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Hierarchical combinations involving metal-ligand interactions and host-guest interactions can consolidate building blocks with unique functions into material properties. This study reports the construction and hierarchical self-assembly of multifunctional trinuclear AuI tricarbene complex containing three crown ether units and three ferrocene units. Host-guest interactions between the multifunctional trinuclear AuI tricarbene complex and organic ammonium salts were investigated, revealing that crown ether-based host-guest interactions can effectively regulate the electrochemical properties of the complex. Utilizing bisammonium salt as the cross-linker and multifunctional trinuclear AuI tricarbene complex as the core, a stimuli-responsive and self-healing supramolecular gel with different functional units was obtained.
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In the prefabricated construction industry, consumers are sensitive to the construction delivery time, and different power structures are very common. This research uses methods of Stackelberg game, Nash game and supply chain coordination, introduces a manufacturer crashing strategy into a prefabricated construction supply chain and investigates the assembler pricing, manufacturer crashing, and supply chain coordination strategies under three different power structures. It finds that adopting a crashing strategy improves the supply chain's profit, while the dynamic wholesale price contract achieves supply chain coordination. Meanwhile, when consumer time and price sensitivity are low, it is easier to achieve high profits in the supply chain under unequal power distribution. Conversely, the supply chain profit is higher in the case of a Nash game. This study innovatively introduces the thought of power structure and crashing strategy into the prefabricated construction supply chain, and provides the optimal price and delivery time under three different power structures for prefabricated construction enterprises and realizes supply chain coordination. The conclusion can provide decision suggestions for the prefabricated construction enterprises under different competitive environments.
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Indústria da Construção , Hepatopatia Gordurosa não Alcoólica , Humanos , Comércio/métodos , Custos e Análise de Custo , Contratos , Comportamento do ConsumidorRESUMO
As key regulators of gene function, long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are generally accepted to be involved in lung cancer pathogenesis and progression. Recent research has clarified the phenomenon of metabolic reprogramming in lung cancer because of its significant role in tumor proliferation, migration, invasion, metastasis, and other malignant biological behaviors. Emerging evidence has also shown a relationship between the aberrant expression of lncRNAs and circRNAs and metabolic reprogramming in lung cancer tumorigenesis. This review provides insight regarding the roles of different lncRNAs and circRNAs in lung cancer metabolic reprogramming, by how they target transporter proteins and key enzymes in glucose, lipid, and glutamine metabolic signaling pathways. The clinical potential of lncRNAs and circRNAs as early diagnostic biomarkers and components of therapeutic strategies in lung cancer is further discussed, including current challenges in their utilization from the bench to the bedside and how to adopt a proper delivery system for their therapeutic use.
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Neoplasias Pulmonares , RNA Longo não Codificante , Biomarcadores , Humanos , Neoplasias Pulmonares/patologia , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de SinaisRESUMO
Lung cancer is one of the main cancer types due to its persistently high incidence and mortality, yet a simple and effective prognostic model is still lacking. This study aimed to identify independent prognostic genes related to the heterogeneity of lung adenocarcinoma (LUAD), generate a prognostic risk score model, and construct a nomogram in combination with other pathological characteristics to predict patients' overall survival (OS). A significant amount of data pertaining to single-cell RNA sequencing (scRNA-seq), RNA sequencing (RNA-seq), and somatic mutation were used for data mining. After statistical analyses, a risk scoring model was established based on eight independent prognostic genes, and the OS of high-risk patients was significantly lower than that of low-risk patients. Interestingly, high-risk patients were more sensitive and effective to immune checkpoint blocking therapy. In addition, it was noteworthy that CCL20 not only affected prognosis and differentiation of LUAD but also led to poor histologic grade of tumor cells. Ultimately, combining risk score, clinicopathological information, and CCL20 mutation status, a nomogram with good predictive performance and high accuracy was established. In short, our research established a prognostic model that could be used to guide clinical practice based on the constantly updated big multi-omics data. Finally, this analysis revealed that CCL20 may become a potential therapeutic target for LUAD.
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The upregulation of lipid metabolism is considered one of the most common characteristic changes in tumor cells. In this study, the effects of phosphanegold(I) thiolate complexes on the regulation of lipid metabolism in lung cancer cells were investigated. Six novel phosphanegold(I) thiolate complexes capable of inhibiting lung cancer cell growth both in vitro and in vivo were synthesized and characterized. These complexes significantly inhibited the activity of thioredoxin reductases and impaired the normal structure and function of mitochondria, leading to an accumulation of internal reactive oxygen species. In addition, they markedly inhibited key enzymes involved in de novo lipid synthesis, including sterol regulatory element-binding proteins, fatty acid synthase, and adenosine triphosphate citrate lyase, thus reducing endogenous fatty acid and phospholipid synthesis. Both approaches suppressed lipid droplets storage and ultimately induced apoptosis in lung cancer cells. Interestingly, pretreatment with N-acetyl-l-cysteine and free fatty acids partially reversed the inhibitory effect of phosphanegold(I) thiolate complexes on lung cancer cells. These results are the first to indicated that gold(I) complexes are promising candidates for targeting lipid metabolism in lung cancer treatment strategies.
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Lipogênese , Neoplasias Pulmonares , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Humanos , Metabolismo dos Lipídeos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
In the past decades, apoptosis has been the most well-studied regulated cell death (RCD) that has essential functions in tissue homeostasis throughout life. However, a novel form of RCD called necroptosis, which requires receptor-interacting protein kinase-3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has recently been receiving increasing scientific attention. The phosphorylation of RIPK3 enables the recruitment and phosphorylation of MLKL, which oligomerizes and translocates to the plasma membranes, ultimately leading to plasma membrane rupture and cell death. Although apoptosis elicits no inflammatory responses, necroptosis triggers inflammation or causes an innate immune response to protect the body through the release of damage-associated molecular patterns (DAMPs). Increasing evidence now suggests that necroptosis is implicated in the pathogenesis of several human diseases such as systemic inflammation, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, neurological diseases, and cancer. This review summarizes the emerging insights of necroptosis and its contribution toward the pathogenesis of lung diseases.
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Metal-organic frameworks (MOFs) consisting of organic radicals are of great interest because they have exhibited unique and intriguing optical, electronic, magnetic, and chemo-catalytic properties, and thus have demonstrated great potential applications in optical, electronic, and magnetic devices, and as catalysts. However, the preparation of MOFs bearing stable organic radicals is very challenging because most organic radicals are highly reactive and difficult to incorporate into the framework of MOFs. Herein we reported a post-synthetic modification strategy to prepare a novel MOF containing phenazine radical cations, which was used as heterogeneous catalyst for aza-Diels-Alder reaction. The zinc-based metal-organic framework Zn2 (PHZ)2 (dabco) (N) was successfully synthesized from 5,10-di(4-benzoic acid)-5,10-dihydrophenazine (PHZ), triethylene diamine (dabco) with Zn(NO3 )2 â 6H2 O by solvothermal method. The as-synthesized MOF N was partially oxidized by AgSbF6 to form MOF R containing â¼10% phenazine radical cation species. The resultant MOF R was found to keep the original crystal type of N and very persistent under ambient conditions. Consequently, MOF R was successfully employed in radical cation-catalyzed aza-Diels-Alder reactions with various imine substrates at room temperature with high reaction conversion. Moreover, heterogeneous catalyst MOF R was reusable up to five times without much loss of catalytic activity, demonstrating its excellent stability and recyclability. Therefore, the post-synthetic modification developed in this work is expected to become a versatile strategy to prepare radical-based MOFs for the application of heterogeneous catalysts in organic synthesis.
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In the assistive research area, human-computer interface (HCI) technology is used to help people with disabilities by conveying their intentions and thoughts to the outside world. Many HCI systems based on eye movement have been proposed to assist people with disabilities. However, due to the complexity of the necessary algorithms and the difficulty of hardware implementation, there are few general-purpose designs that consider practicality and stability in real life. Therefore, to solve these limitations and problems, an HCI system based on electrooculography (EOG) is proposed in this study. The proposed classification algorithm provides eye-state detection, including the fixation, saccade, and blinking states. Moreover, this algorithm can distinguish among ten kinds of saccade movements (i.e., up, down, left, right, farther left, farther right, up-left, down-left, up-right, and down-right). In addition, we developed an HCI system based on an eye-movement classification algorithm. This system provides an eye-dialing interface that can be used to improve the lives of people with disabilities. The results illustrate the good performance of the proposed classification algorithm. Moreover, the EOG-based system, which can detect ten different eye-movement features, can be utilized in real-life applications.
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Eletroculografia , Dispositivos Eletrônicos Vestíveis , Algoritmos , Movimentos Oculares , Humanos , Movimento , Processamento de Sinais Assistido por Computador , Interface Usuário-ComputadorRESUMO
AIMS: Hepatocyte necroptosis is a critical event in the progression of non-alcoholic fatty liver disease (NAFLD). Obstructive sleep apnea hypopnea syndrome (OSAHS) and chronic intermittent hypoxia (CIH) may be linked with the pathogenesis and the severity of NAFLD. However, the potential role of necroptosis in OSAHS-associated NAFLD has not been evaluated. The present study investigated whether IH could affect NAFLD progression through promoting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis, oxidative stress, and inflammatory response, and further elucidated the underlying molecular mechanisms. MAIN METHODS: LO2 cells were treated with palmitic acid (PA) and subjected to IH, and necroptosis, oxidative stress, and inflammation were assessed. The high-fat choline-deficient (HFCD)-fed mouse model was also used to assess the effects of CIH in experimental NAFLD in vivo. KEY FINDINGS: In this study, we found that RIPK3-mediated necroptosis was activated both in the PA plus IH-treated LO2 cells and liver of HFCD/CIH mice, and which could trigger oxidative stress and inflammatory response by decreasing Nrf2 and increasing p-P65. RIPK3 downregulation significantly reduced hepatocyte necroptosis, and ameliorated oxidative stress and inflammation through modulating Nrf2/NFκB pathway in vitro and vivo. Similarly, pretreatment with TBHQ, an activator of Nrf2, effectively blocked the generation of oxidative productions and inflammatory cytokines. In addition, RIPK3 inhibitor GSK-872 or TBHQ administration obviously alleviated hepatic injury, including histology, transaminase activities, and triglyceride contents in vivo. SIGNIFICANCE: IH aggravates NAFLD via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway, and which should be considered as a potential therapeutic strategy for the treatment of NAFLD with OSASH.
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Hipóxia/complicações , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Necroptose , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Apneia Obstrutiva do Sono/complicações , Animais , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Hidroquinonas/farmacologia , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estresse Oxidativo , Ácido Palmítico/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Apneia Obstrutiva do Sono/metabolismoRESUMO
The topic of noncovalent spin-spin interactions is of increasing general interest in supramolecular radical chemistry. In this report, a series of exo- and endo-TEMPO radical-functionalized metallacycles 1-4 and metallacages 5 and 6 were constructed via coordination-driven self-assembly, wherein the number, location, and distance of the spins were precisely controlled. Their intriguing spin-spin interactions were systematically investigated by electron paramagnetic resonance (EPR) and were well interpreted at the molecular level assisted by X-ray crystallography analysis. The results revealed their distinct spin-spin interactions in the solution state, wherein the spin-spin interaction of metallacycle 3 was much stronger than that of the other five assemblies mainly due to its shorter intramolecular spin-spin distance. In the solid state, 1-6 exhibited obvious spin-spin (dipole-dipole) interactions because of the close arrangement of TEMPO units as indicated in their single crystals. Specifically, a large zero-field splitting (ZFS; D = 17.5 mT) was observed in the crystalline form of metallacycle 4, which arose from the strong intermolecular spin-spin coupling. Interestingly, when the counterion of PF6- in 4 was changed to BF4-, the BF4- counterion analog 4a also exhibited a large ZFS, but the ZFS originated from the intramolecular spin-spin interaction due to a small variation in its crystal conformation. Moreover, the reversible on-off switching of the ZFS in 4 and 4a via the crystal-to-amorphous transformation induced by mechanical grinding and solvent vapor stimuli was also successfully realized. The unique and controllable inter- and intramolecular spin-spin interactions in this work reveal new insights for the understanding and manipulation of spin-spin interactions and may open up a new way to develop organic spin materials in the future.
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It has been a challenging topic and perpetual task to design and synthesize covalent macrocycles with characteristic self-assembling behaviors and excellent host-guest properties in supramolecular chemistry. Herein, we present a family of macrocyclic diphenylamine[n]arenes (DPA[n]s, n = 3-7) consisting of methyldiphenylamine units through a facile one-pot synthesis strategy. Unlike many other reported macrocyclic arenes, the resultant non-planar DPA[n]s feature intrinsic π-π stacking interactions, interesting self-assembling behaviors and ethene/ethyne capture properties. Specifically, strong multiple intermolecular edge-to-face aromatic interactions in DPA[3] have been systematically investigated both in solid and solution states. The intriguing findings on the intermolecular edge-to-face stacking interaction mode in the macrocycle would further highlight the importance of noncovalent π-π interaction in supramolecular self-assembly. This study will also shed light on the macrocyclic and supramolecular chemistry and, we expect, will provide a direction for design and synthesis of covalent macrocycles in this area.
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Chloroplast genomes have been widely considered an informative and valuable resource for molecular marker development and phylogenetic reconstruction in plant species. This study evaluated the complete chloroplast genomes of the traditional Chinese medicine Gleditsia sinensis and G. japonica, an adulterant of the former. The complete chloroplast genomes of G. sinensis and G. japonica were found to be of sizes 163,175 bp and 162,391 bp, respectively. A total of 111 genes were identified in each chloroplast genome, including 77 coding sequences, 30 tRNA, and 4 rRNA genes. Comparative analysis demonstrated that the chloroplast genomes of these two species were highly conserved in genome size, GC contents, and gene organization. Additionally, nucleotide diversity analysis of the two chloroplast genomes revealed that the two short regions of ycf1b were highly diverse, and could be treated as mini-barcode candidate regions. The mini-barcode of primers ZJ818F-1038R was proven to precisely discriminate between these two species and reflect their biomass ratio accurately. Overall, the findings of our study will shed light on the genetic evolution and guide species identification of G. sinensis and G. japonica.
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Cloroplastos/genética , Código de Barras de DNA Taxonômico , Genoma de Cloroplastos/genética , Gleditsia/genética , Mapeamento Cromossômico , Código de Barras de DNA Taxonômico/métodos , Genes de Plantas/genética , Genoma de Planta/genética , Filogenia , RNA Ribossômico/genética , RNA de Transferência/genéticaRESUMO
Ligustrum quihoui (L. quihoui) is an important hedge material for landscaping and also possesses medicinal value. To generate genomic resources for better understanding the evolutionary history of this important plant, the organelle genomes of L. quihoui are de novo assembled and functionally annotated. Compared with other Oleaceae species, the 163,069 bp chloroplast genome of L. quihoui exhibits a typical quadripartite structure with highly conserved gene content and gene order, while the 848,451 bp mitochondrial genome of L. quihoui exhibits highly divergent genome size and gene content. Codon usage analyses show that genes related with photosynthesis and mitochondrial respiratory chain show inconsistent codon biases. A total of 48,760 bp transposable elements (TEs) fragments and 41,887 bp chloroplast-like sequences are found in the L. quihoui mitochondrial genome. A striking discrepancy of RNA editing between the two organelle genomes is found in L. quihoui, in which 146 mitochondrial editing sites coexist with only 43 such sites in chloroplast. Based on DNA and RNA-Seq data, we propose that GTG may act as the start codon of mitochondrial rpl16 in Oleaceae species. Phylogenetic analysis based on chloroplast genome shows that L. quihoui and L. japonicum form a sister clade within the genus Ligustrum.
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Elementos de DNA Transponíveis/genética , Genoma de Cloroplastos , Genoma Mitocondrial , Ligustrum/genética , Transcriptoma/genética , Sequência de Bases , Mapeamento Cromossômico , Códon/genética , Genes de Plantas , Genoma de Cloroplastos/genética , Genoma Mitocondrial/genética , Funções Verossimilhança , Anotação de Sequência Molecular , Filogenia , Edição de RNA/genéticaRESUMO
In this study, we characterized the transcriptome and chloroplast genome of Glycyrrhiza inflata and performed comparative analyses with G. uralensis and G. glabra. 60,541unigenes were obtained from the transcriptome of G. inflata. The results of function annotation revealed a similar distribution of functional categories among three licorice species. By comparing chloroplast genomes of licorice species, it was demonstrated that the structure and the length of genome as well as gene content and gene order were highly similar. The phylogenetic tree, constructed with the mixed data of transcriptome and chloroplast genome, elucidated that G. inflata and G. glabra had a closer relationship than G. uralensis. Six regions were suggested as potential markers for the identification of three licorice species. In each licorice species, two unigenes were homologous to reference flavonol synthase. For G. inflata, 48 and 21 RNA editing sites were detected by PREP-Cp program and RNA-Seq data mapping, respectively.
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Genoma de Cloroplastos , Glycyrrhiza/genética , Transcriptoma , Glycyrrhiza/classificação , Repetições de Microssatélites , Anotação de Sequência Molecular , Oxirredutases/genética , Filogenia , Proteínas de Plantas/genética , Edição de RNARESUMO
BACKGROUNDFatal cases of COVID-19 are increasing globally. We retrospectively investigated the potential of immunologic parameters as early predictors of COVID-19.METHODSA total of 1018 patients with confirmed COVID-19 were enrolled in our 2-center retrospective study. Clinical feature, laboratory test, immunological test, radiological findings, and outcomes data were collected. Univariate and multivariable logistic regression analyses were performed to evaluate factors associated with in-hospital mortality. Receiver operator characteristic (ROC) curves and survival curves were plotted to evaluate their clinical utility.RESULTSThe counts of all T lymphocyte subsets were markedly lower in nonsurvivors than in survivors, especially CD8+ T cells. Among all tested cytokines, IL-6 was elevated most significantly, with an upward trend of more than 10-fold. Using multivariate logistic regression analysis, IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL were found to be associated with in-hospital mortality after adjusting for confounding factors. Groups with IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL had a higher percentage of older and male patients as well as a higher proportion of patients with comorbidities, ventilation, intensive care unit admission, shock, and death. Furthermore, the receiver operating curve of the model combining IL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) displayed a more favorable discrimination than that of the CURB-65 score. The Hosmer-Lemeshow test showed a good fit of the model, with no statistical significance.CONCLUSIONIL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) are 2 reliable prognostic indicators that accurately stratify patients into risk categories and predict COVID-19 mortality.FundingThis work was supported by funding from the National Natural Science Foundation of China (no. 81772477 and 81201848).
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Linfócitos T CD8-Positivos , Infecções por Coronavirus/imunologia , Mortalidade Hospitalar , Interleucina-6/imunologia , Pneumonia Viral/imunologia , Idoso , Área Sob a Curva , Betacoronavirus , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Interleucina-10/imunologia , Interleucina-8/imunologia , Modelos Logísticos , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Prognóstico , Curva ROC , Receptores de Interleucina-2/imunologia , Estudos Retrospectivos , SARS-CoV-2 , Fator de Necrose Tumoral alfa/imunologiaRESUMO
We herein present a new family of crown ether-based covalent organic frameworks (CE-COFs) for the first time. The CE-COFs show excellent phase-transfer catalytic performance in various nucleophilic substitution reactions.
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Objective: Traditional Chinese Medicines (TCMs), as well as physiotherapy and chemical drugs, are recommended for the treatment of cervical spondylosis by Chinese guidelines for cervical spondylosis diagnosis and treatment. The aim of this study was to evaluate whether TCM Jingshu Granules are cost-effective in patients with cervical radiculopathy in China. Methods: A multicenter, double-blinded, randomized placebo-controlled trial was performed. A total of 480 patients were recruited from 14 tertiary hospitals in China and were randomly divided into an experimental group (Jingshu Granules) or control group (placebo) at a 3:1 ratio. All patients received 4 weeks of treatment. Clinical outcomes and cost data were collected during the trial, including the neck disability index (NDI), visual analog scale (VAS) of pain, VAS of numbness, 36-Item Short Form Health Survey (SF-36) score, willingness to pay (WTP) for VAS of pain, direct medical costs, and transport costs. From a social perspective, a decision-tree model and cost-effectiveness analysis were conducted. Results: The treatment group has a significant advantage in reducing NDI (9.41 ± 10.51 vs. 4.83 ± 8.43, p < 0.05), VAS of pain (22.72 ± 15.08 vs. 12.86 ± 13.45, p < 0.05), and VAS of numbness (16.96 ± 17.53 vs. 11.64 ± 16.54, p < 0.05), respectively, while there was no significant difference in the improvement of quality of life (QoL; SF-36 score, p > 0.05). The expected mean cost of the experimental group was 1144.34 yuan, and the effective rates were 57.9% for NDI and 72.9% for VAS of pain. The expected mean cost of the control group was 767.41 yuan, and the effective rates were 33.3% for NDI and 51.6% for VAS of pain. For the primary indicators (VAS of pain and NDI), the incremental cost-effectiveness ratio was 17.69 and 15.32, respectively. The WTP per efficacy for pain resolution of patients was 19.10 yuan. Setting the WTP as threshold, Jingshu Granules were found to be a cost-effectiveness strategy, and sensitivity analysis showed that the effective rates and inspection fees of both groups had a greater impact on the results of both groups. Conclusions: Jingshu Granules were shown to be effective for treating patients with cervical radiculopathy. This treatment was found to be cost-effective when considering VAS of pain and NDI as clinical outcome indicators compared to no treatment (placebo). A clinical study with longer duration or real world study is needed to determine the impact on QoL of patients in the future.