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Deubiquitylases (DUBs) have emerged as promising targets for cancer therapy due to their role in stabilizing substrate proteins within the ubiquitin machinery. Here, we identified ubiquitin-specific protease 26 (USP26) as an oncogene via screening prognostic DUBs in breast cancer. Through in vitro and in vivo experiments, we found that depletion of USP26 inhibited breast cancer cell proliferation and invasion, and suppressed tumor growth and metastasis in nude mice. Further investigation identified co-chaperone Bcl-2-associated athanogene 3 (BAG3) as the direct substrate of USP26, and ectopic expression of BAG3 partially reversed antitumor effect induced by USP26 knockdown. Mechanistically, the lysine acetyltransferase Tip60 targeted USP26 at K134 for acetylation, which enhanced USP26 binding affinity to BAG3, leading to BAG3 deubiquitination and increased protein stability. Importantly, we employed a structure-based virtual screening and discovered a drug-like molecule called 5813669 that targets USP26, destabilizing BAG3 and effectively mitigating tumor growth and metastasis in vivo. Clinically, high expression levels of USP26 were correlated with elevated BAG3 levels and poor prognosis in breast cancer patients. Overall, our findings highlight the critical role of USP26 in BAG3 protein stabilization and provide a promising therapeutic target for breast cancer.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Neoplasias da Mama , Cisteína Endopeptidases , Animais , Feminino , Humanos , Camundongos , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/genética , Progressão da Doença , Camundongos Nus , Prognóstico , Estabilidade Proteica , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This study aimed to evaluate whether palliative surgery for metastatic lesion could provide a survival benefit in metastatic breast cancer (MBC) patients with solitary metastasis. De novo MBC patients with solitary distant lesions were enrolled utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to form matched pairs of the surgery group and the non-surgery group. The breast cancer-specific survival (BCSS) and overall survival (OS) outcomes between the 2 groups were compared in the following 3 sample models: the entire cohort of MBC (7665 cases); subgroups of patients with different isolated metastatic organs; and subgroups of patients with different molecular subtypes for each isolated metastatic organ. Compared with the Non-surgery group, the surgery group showed better BCSS and OS before PSM (HRâ =â 0.88, 95% CIâ =â 0.79-0.99, Pâ =â .04 and HRâ =â 0.85, 95% CIâ =â 0.76-0.95, Pâ =â .006, respectively). After PSM, palliative surgery still provided an OS benefit in patients with brain metastasis and lung metastasis (HRâ =â 0.59, 95% CIâ =â 0.37-0.95, Pâ =â .01 and HRâ =â 0.64, 95% CIâ =â 0.45-0.90, Pâ =â .02, respectively). Likewise, a better BCSS benefit was also found in the subset of patients with brain metastasis (HRâ =â 0.61, 95% CIâ =â 0.38-1.00, Pâ =â .01). Further stratification analysis indicated that patients with the luminal A subtype with brain metastasis have a better BCSS (HRâ =â 0.36, 95% CIâ =â 0.16-0.79, Pâ =â .04) and OS (HRâ =â 0.37, 95% CIâ =â 0.18-0.75, Pâ =â .03) after undergoing palliative surgery than nonsurgical treatment. Our study originality showed that palliative surgery for metastatic lesion could improve survival prognosis in patients with special single-organ metastasis and specific molecular subtypes. More clinical studies are needed to determine whether palliative surgery should be performed in MBC patients.
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Neoplasias da Mama , Cuidados Paliativos , Pontuação de Propensão , Programa de SEER , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/mortalidade , Cuidados Paliativos/métodos , Pessoa de Meia-Idade , Idoso , Metástase Neoplásica , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/mortalidade , Adulto , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estudos RetrospectivosRESUMO
PoRVA and PEDV coinfections are extremely common in clinical practice. Although coinfections of PoRVA and PEDV are known to result in increased mortality, the underlying mechanism remains unknown. Here, we found that PoRVA infection promoted PEDV infection in vivo and in vitro and that PoRVA G9P[23] (RVA-HNNY strain) enhanced PEDV replication more significantly than did PoRVA G5P[7] (RVA-SXXA strain). Metabolomic analysis revealed that RVA-HNNY more efficiently induced an increase in the intracellular glutamine content in porcine small intestinal epithelial cells than did RVA-SXXA, which more markedly promoted ATP production to facilitate PEDV replication, whereas glutamine deprivation abrogated the effect of PoRVA infection on promoting PEDV replication. Further studies showed that PoRVA infection promoted glutamine uptake by upregulating the expression of the glutamine transporter protein SLC1A5. In SLC1A5 knockout cells, PoRVA infection neither elevated intracellular glutamine nor promoted PEDV replication. During PoRVA infection, the activity and protein expression levels of glutamine catabolism-related enzymes (GLS1 and GLUD1) were also significantly increased promoting ATP production through glutamine anaplerosis into the TCA cycle. Consistent with that, siRNAs or inhibitors of GLS1 and GLUD1 significantly inhibited the promotion of PEDV replication by PoRVA. Notably, RVA-HNNY infection more markedly promoted SLC1A5, GLS1 and GLUD1 expression to more significantly increase the uptake and catabolism of glutamine than RVA-SXXA infection. Collectively, our findings illuminate a novel mechanism by which PoRVA infection promotes PEDV infection and reveal that the modulation of glutamine uptake is key for the different efficiencies of PoRVA G9P[23] and PoRVA G5P[7] in promoting PEDV replication.
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Glutamina , Vírus da Diarreia Epidêmica Suína , Replicação Viral , Glutamina/metabolismo , Animais , Replicação Viral/fisiologia , Suínos , Vírus da Diarreia Epidêmica Suína/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Doenças dos Suínos/metabolismo , Chlorocebus aethiopsRESUMO
Dragon fruit peel, often discarded, is a valuable source of commercial pectin. This study investigates different extraction methods, including cold-water (CW), hot-water (HW), ultrasound (US), and novel enzyme extraction (xylanase: EZX), to extract pectins from dragon fruit peel and compare their characteristics. The pectin yield ranged from 10.93% to 20.22%, with significant variations in physicochemical properties across methods (p < 0.05). FTIR analysis revealed that extraction methods did not alter the primary structural configuration of the pectins. However, molecular weights (Mws) varied significantly, from 0.84 to 1.21 × 103 kDa, and the degree of esterification varied from 46.82% to 51.79% (p < 0.05). Monosaccharide analysis identified both homogalacturonan (HG) and rhamnogalacturonan-I (RG-I) pectic configurations in all pectins, predominantly comprising galacturonic acid (77.21-83.12 %mol) and rhamnose (8.11-9.51 %mol), alongside minor side-chain sugars. These properties significantly influenced pectin functionalities. In the aqueous state, a higher Mw impacted viscosity and emulsification performance, while a lower Mw enhanced antioxidant activities and promoted the prebiotic function of pectin (Lactis brevies growth). This study highlights the impact of extraction methods on dragon fruit peel pectin functionalities and their structure-function relationship, providing valuable insights into predicting dragon fruit peel's potential as a food-grade ingredient in various products.
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Background: Glioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy. Methods: We identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves. Results: The levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas. Conclusion: Heightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. Blocking TBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.
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Neoplasias Encefálicas , Glioma , Imunoterapia , Humanos , Biomarcadores , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/imunologia , Glioma/terapia , Proteínas Ativadoras de GTPase/genética , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Sepsis is a multisystem disease characterized by dysregulation of the host immune response to infection. Immune response kinetics play a crucial role in the pathogenesis and progression of sepsis. Macrophages, which are known for their heterogeneity and plasticity, actively participate in the immune response during sepsis. These cells are influenced by the ever-changing immune microenvironment and exhibit two-sided immune regulation. Recently, the immunomodulatory function of mesenchymal stem cells (MSCs) in sepsis has garnered significant attention. The immune microenvironment can profoundly impact MSCs, prompting them to exhibit dual immunomodulatory functions akin to a double-edged sword. This discovery holds great importance for understanding sepsis progression and devising effective treatment strategies. Importantly, there is a close interrelationship between macrophages and MSCs, characterized by the fact that during sepsis, these two cell types interact and cooperate to regulate inflammatory processes. This review summarizes the plasticity of macrophages and MSCs within the immune microenvironment during sepsis, as well as the intricate crosstalk between them. This remains an important concern for the future use of these cells for immunomodulatory treatments in the clinic.
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Células-Tronco Mesenquimais , Sepse , Humanos , Macrófagos , Imunomodulação , Imunidade , Células-Tronco Mesenquimais/metabolismo , Sepse/metabolismoRESUMO
The world is currently facing urgent climate and environmental issues, such as global warming, ecosystem collapse, and energy shortages. In this context, this study selected data from 2000 to 2021 and employed the Method of Moment Quantile Regression (MMQR) to thoroughly investigate the impact of renewable energy consumption, economic complexity, and geopolitical risks on the ecological footprint of the Group of Twenty (G20) countries. The results indicate that in countries with lower quantiles, renewable energy consumption significantly reduces the ecological footprint, whereas its effect is not prominent in countries with higher quantiles. Economic complexity has a negative impact on the ecological footprint, and this impact becomes stronger as the quantile of the ecological footprint rises. Additionally, economic complexity moderates the effect of renewable energy on the ecological footprint. Geopolitical risks facilitate the growth of the ecological footprint. Likewise, robustness tests such as DOLS, FMOLS, and quantile regression confirm these estimates in the same framework. This study has conducted a profound analysis of global environmental issues, offering innovative perspectives and recommendations for achieving goals related to sustainable energy utilization, mitigating climate change, and improving the ecological environment. The findings of this research will guide policymakers in G20 countries to adopt more effective environmental protection measures, thereby contributing to the construction of a sustainable future.
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Ecossistema , Resiliência Psicológica , Desenvolvimento Econômico , Dióxido de Carbono , Energia RenovávelRESUMO
BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear. METHODS: Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models. RESULTS: In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8+ T cells and reshaping the immune landscape and cytokine milieu of tumors in vivo. Mechanistically, inhibiting ALDH2-mediated metabolism of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. As a result, the cytotoxic function of CD8+ T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment. CONCLUSIONS: Our data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-κB/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy.
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Linfócitos T CD8-Positivos , Neoplasias , Animais , Camundongos , Aldeído Desidrogenase/metabolismo , Aldeídos/metabolismo , Aldeídos/farmacologia , Linfócitos T CD8-Positivos/metabolismo , NF-kappa B/metabolismo , Nucleotídeos , Evasão Tumoral , Microambiente TumoralRESUMO
BACKGROUND: Contrast-enhanced ultrasound (CEUS) has been recently used for the assessment of cervical lymph node metastasis (LNM) to guide surgical operation in patients with papillary thyroid carcinoma (PTC). However, the specificity and sensitivity of CEUS reported from previous studies are not consistent. The objective of this study was to evaluate the diagnostic value of CEUS for the metastasis of cervical lymph nodes in PTC patients based on data from one regional central hospital. METHODS: The diagnostic value of CEUS in preoperative LNM of PTC patients was concluded by comparing the results of CEUS on lymph node status with postoperative pathology examination. In addition, this study conducted hierarchical analysis of PTC patients to explore whether tumor size, different lymph node regions, and Hashimoto's thyroiditis influence the assessment of CEUS. RESULTS: This research study ultimately enrolled 965 PTC patients, including 266 males and 699 females with a mean age of 42.27 ± 11.34 years. A total of 527 patients were considered clinical-node negative, and 438 were clinical-node positive before surgery. The specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of CEUS in the assessment of LNM in PTC patients were 56.00%, 71.00%, 57.06%, 69.76% and 62.59%, respectively. For central and lateral lymph nodes, the accuracy of CEUS in PTC patients was 49.43% and 54.30%, respectively. In addition, it was shown that the accuracy of CEUS in PTC patients with Hashimoto's thyroiditis (HT) slightly decreased to 58.44%, and the accuracy of CEUS in PTC patients with non-HT in turn increased to 64.17%. The accuracy of CEUS in non-papillary thyroid microcarcinoma (PTMC) and PTMC patients was 65.68% and 61.24%, respectively. The accuracy of CEUS in predicting central LNM was significantly different between PTC patients with or without HT (P < 0.001) in this study but not for lateral lymph nodes (P = 0.114). CONCLUSION: The accuracy of CEUS in the assessment of LNM in PTC is not consistently satisfactory, especially for central lymph nodes, small tumor diameters, or patients with HT. More diagnostic technologies for abnormal lymph nodes should be considered in PTC patients.
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Doença de Hashimoto , Neoplasias da Glândula Tireoide , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/patologia , Estudos Retrospectivos , Metástase Linfática/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Ultrassonografia/métodos , Doença de Hashimoto/patologiaRESUMO
BACKGROUND: Thrombopoietin receptor agonists (TPO-RAs) have emerged as a recommended treatment for children with persistent and/or chronic immune thrombocytopenic purpura (ITP). The purpose of this study was to evaluate the cost-effectiveness of TPO-RAs relative to treatment without TPO-RAs (non-TPO-RAs/usual care) for ITP in children who do not respond to first-line therapy and in whom splenectomy is not recommended in Ontario, Canada, from a hospital payer perspective. PROCEDURE: A 2-year Markov model with an embedded decision tree was used. Data on medications used, dose, response rate, bleeding, and emergency treatment events were collected from the Hospital for Sick Children in Toronto. The health outcomes were described in quality-adjusted life-years (QALYs). Health-state utilities were derived from the peer-reviewed literature. Scenario analyses, deterministic, and probabilistic sensitivity analyses were conducted. Economic costs were measured in 2021 Canadian dollars ($1.00 = US$0.80) RESULTS: TPO-RAs are estimated to result in an increased cost of $27,118 and a QALY gain of 0.21 compared to non-TPO-RAs over a 2-year horizon, resulting in an incremental cost-effectiveness ratio (ICER) of $129,133. In a 5-year scenario analysis, the ICER fell to $76,403. In the probabilistic sensitivity analysis, TPO-RAs exhibit a 40.0% probability of being cost-effective at a conventional ($100,000) willingness-to-pay threshold per QALY gained. CONCLUSIONS: Further assessment of the long-term efficacy of TPO-RAs is warranted to obtain more precise long-term estimates. As the costs of TPO-RAs decline with the introduction of generic formulations, TPO-RAs may be increasingly cost-effective.
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A rhodium-catalyzed asymmetric ring expansion of 4/5-spirosilafluorenes with terminal alkynes has been developed using sterically demanding binaphthyl phosphoramidite ligand. The reaction is not only strategically distinct from cyclization or cycloaddition but also showcases the first enantioselective synthesis of axially chiral 6/5-spirosilafluorenes.
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BACKGROUND: Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic. METHODS: Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival. RESULTS: Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8+ T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4+ T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects. CONCLUSIONS: Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy.
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Imunoterapia , Neoplasias , Animais , Camundongos , Linfócitos T Citotóxicos , Linfócitos T CD8-Positivos , Preparações Farmacêuticas , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Exploring an effective sepsis screening tool that can be widely implemented is important for improving the prognosis of sepsis worldwide. This study aimed to develop a new simple screening tool for sepsis (LIP scoring system) that includes the peripheral blood lymphocyte count, international normalized ratio, and procalcitonin level. In a single-center, prospective, observational study, 444 acute sepsis inpatients and 444 nonsepsis inpatients were ultimately included based on the Sepsis-3 and exclusion criteria. The differences in the Lym, INR, PCT level and other clinical biomarkers were compared between the two groups. Univariable and multivariable logistic regression analyses and receiver operating characteristic analysis were used to establish a LIP screening tool for sepsis with a combination of biomarkers. The Kappa and McNemar tests were used to evaluate the differences between the LIP screening results (LIP score ≥ 3) and Sepsis-3 criteria (SOFA score ≥ 2). Logistic regression analysis showed that the lymphocyte count, INR, PCT level, platelets, neutrophil/lymphocyte ratio (NLR) and prothrombin time (PT) were independent risk factors for the development of sepsis. The ROC analysis showed that the lymphocyte count, INR, and PCT level had high area under the ROC curve values (AUROC (95% CI): Lym 0.84 (0.810-0.860), INR 0.921 (0.902-0.938), PCT level 0.928 (0.909-0.944)). The LIP tool had satisfactory screening efficacy for sepsis (sensitivity, 92.8%; specificity, 94.1%), and a LIP score equal to or greater than 3 points had good agreement with Sepsis-3 criteria in the diagnosis of sepsis (Kappa = 0862 in the Kappa test and P = 0.512 in the McNemar test). The LIP tool has satisfactory sensitivity and specificity for sepsis screening, and it can be used for rapid screening of patients with sepsis in outpatient and emergency departments or in economically underdeveloped areas with limited resources.
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Pró-Calcitonina , Sepse , Humanos , Coeficiente Internacional Normatizado , Estudos Prospectivos , Contagem de Linfócitos , Sepse/diagnóstico , BiomarcadoresRESUMO
Silaspiranes have attracted particular attention due to their chiral spiro-silicon center, which serves as an ideal carbon isostere and can endow spiro-analogs with distinct properties. Distinct from previously reported cyclization or cycloaddition strategies to form 5/5-silaspiranes, we report herein the asymmetric dual ring expansion of spirosilabicyclobutanes with alkynes to synthesize axially chiral spirosilabicyclohexenes bearing a novel 6/6-silaspirane framework. DFT (density functional theory) calculations provide the deep insight into the origin of the high enantioselectivity controlled by the sterically demanding binaphthyl phosphoramidite ligand. Preliminary studies of chiroptical properties indicate that one of the spirosilabicyclohexene analogs exhibit fluorescence emission, Cotton effects and CPL (circularly polarized luminescence) activity.
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Alcinos , Luminescência , Estereoisomerismo , Ciclização , LigantesRESUMO
Astragalus variabilis is a locoweed of northwest China that can seriously impede livestock development. However, it also plays various ecological roles, such as wind protection and sand fixation. Here, we used an optimized MaxEnt model to predict the distribution of suitable habitat of A. variabilis under current (1970-2000) conditions and future (2021-2080) climate change scenarios based on recent occurrence records. The most important environmental variables (suitability ranges in parentheses) affecting the distribution of A. variabilis were average maximum temperature of February (-2.12-5.34°C), followed by total precipitation of June (2.06-37.33 mm), and topsoil organic carbon (0.36-0.69%). The habitat suitability of A. variabilis was significantly correlated with the frequency of livestock poisoning (p < 0.05). Under current climate conditions, the suitable environment of A. variabilis was distributed in central and western Inner Mongolia, Ningxia, central and northwestern Gansu, central and northwestern Qinghai, and the four basins around the Tianshan Mountains in Xinjiang. Under future climate conditions, the suitable habitat of A. variabilis shifted to higher latitudes and altitudes. No previous studies have used niche models to predict the suitable environment of this species nor analyzed the relationship between the habitat suitability of poisonous plants and the frequency of animal poisoning. Our findings provide new insights that will aid the prevention of livestock animal poisoning and the control of poisonous plants, promote the development of the livestock husbandry industry, and provide basic information that will facilitate the maintenance of the ecological balance of grassland ecosystems.
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Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune "cold" tumor into "hot" tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy.
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Fibroblastos Associados a Câncer , Receptores de Fatores de Crescimento de Fibroblastos , Linfócitos T , Neoplasias de Mama Triplo Negativas , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Quinoxalinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente TumoralRESUMO
BACKGROUND: Sleep curtailment is a serious problem in many societies. Clinical evidence has shown that sleep deprivation is associated with mood dysregulation, formation of false memory, cardio-metabolic risk factors and outcomes, inflammatory disease risk, and all-cause mortality. The affective disorder dysregulation caused by insufficient sleep has become an increasingly serious health problem. However, to date, not much attention has been paid to the mild affective dysregulation caused by insufficient sleep, and there is no clear and standard therapeutic method to treat it. The Xiaoyao Pill is a classic Chinese medicinal formula, with the effect of dispersing stagnated hepatoqi, invigorating the spleen, and nourishing the blood. Therefore, it is most commonly used to treat gynecological diseases in China. In the present study, the effects of the Xiaoyao Pill on affective dysregulation of sleep-deprived mice and its underlying molecular mechanisms were investigated. METHODS: Forty adult female mice were used in the present study. The sleep deprivation model was established by improving the multi-platform water environment method. After 7 consecutive days of sleep deprivation, the mice were administrated low (LXYP, 0.32mg/kg) and high (HXYP, 0.64 mg/kg) doses of the Xiaoyao Pill for two weeks. Then, the body weight, behavioral deficits, and histopathology were evaluated. Meanwhile, the expression of c-fos protein and the concentrations of monoamine neurotransmitters in the hippocampus and prefrontal cortex were determined after two weeks of treatment. RESULTS: Xiaoyao Pill treatment significantly increased body weight and sucrose consumption and decreased the irritability scores of the sleep-deprived mice. Meanwhile, Xiaoyao Pill treatment prevented brain injury and inhibited the expression of c-fos protein in the hippocampus and prefrontal cortex. In addition, HXYP treatment significantly upregulated the levels of NE in the hippocampus and prefrontal cortex (p < 0.01). LXYP treatment significantly up-regulated the levels of 5-HT in the prefrontal cortex. Meanwhile, both HXYP and LXYP treatment significantly upregulated the levels of DA in the prefrontal cortex (p < 0.05 or p < 0.01) of sleep-deprived mice. CONCLUSION: The present study demonstrates that Xiaoyao Pill treatment prevented the behavioral deficits of mice induced by sleep deprivation by promoting the recovery of brain tissue injury and up-regulating the levels of NE, 5-HT, and DA in the brain tissue.
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Lesões Encefálicas , Privação do Sono , Animais , Peso Corporal , Lesões Encefálicas/metabolismo , Medicamentos de Ervas Chinesas , Feminino , Hipocampo , Camundongos , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/farmacologia , Serotonina/metabolismo , Privação do Sono/tratamento farmacológico , Privação do Sono/metabolismoRESUMO
BACKGROUND: Currently, there is a lack of sepsis screening tools that can be widely used worldwide. Pulmonary sepsis can be of sufficient concern to physicians due to their noticeable symptoms, which usually rely less on screening tools. AIM: To investigate the efficiency of the international normalized ratio (INR) for the early rapid recognition of adult nonpulmonary infectious sepsis. METHODS: This is a prospective observational study. A total of 108 sepsis patients and 106 nonsepsis patients were enrolled according to relevant inclusion and exclusion criteria. Commonly used clinical indicators, such as white blood cell, neutrophil count, lymphocyte count, neutrophil-lymphocyte count ratio (NLCR), platelets (PLT), prothrombin time, INR, activated partial thromboplastin time, and quick Sequential "Sepsis-related" Organ Failure Assessment (qSOFA) scores were recorded within 24 h after admission. The diagnostic performances of these clinical indicators were analyzed and compared through multivariate logistic regression analysis, Spearman correlation, and receiver operating characteristic curve analysis. RESULTS: The INR value of the sepsis group was significantly higher than that of the nonsepsis group. INR has superior diagnostic efficacy for sepsis, with an area under the curve value of 0.918, when those preexisting diseases which significantly affect coagulation function were excluded. The diagnostic efficacy of the INR was more significant than that of NLCR, PLT, and qSOFA (P < 0.05). Moreover, INR levels of 1.17, 1.20, and 1.22 could be used to categorize the relative risk of nonpulmonary infections sepsis into three categories: low, medium and high risk, respectively. CONCLUSION: The INR is a promising and easily available biomarker for diagnosis, and it can be used as one of the indicators for early screening of adult nonpulmonary infectious sepsis. When its value is higher than the optimal cutoff value (1.22), high vigilance is required for adult nonpulmonary infectious sepsis.
RESUMO
The long non-coding RNAs (lncRNAs) participate in modulating numerous important cancer phenotypes via formation of RNA-protein complex. TINCR (terminal differentiation-induced lncRNA) modulates cancer cell behavior in many human malignancies, such as hepatocellular carcinoma (HCC). Herein, we proposed to investigate the underlying mechanism by which TINCR regulates HCC progression via formation of RNA-protein. RNA pulldown, LC-MS/MS, bioinformatics analysis, and RNA immunoprecipitation (RIP) assays were employed to identify TINCR-interacting protein TCPTP in HCC cells. The siRNAs for TINCR and TCPTP were transfected into HCC cells. The plasmids encoding full length or the 1-360 nt deletion of TINCR were generated and applied to cell transfection. The CCK-8, colony formation, EdU, wound healing along with transwell assays were employed to examine cell proliferation, apoptosis, migration, and infiltration. Real-time PCR, as well as western blot assays were employed to assess the levels of STAT3 phosphorylation and its target genes. We identified 1-360 nt region of TINCR, which directly bound with the phosphatase domain of TCPTP to inhibit its tyrosine phosphatase activity. Then, the results showed that the increasing of cell growth, migration, infiltration, and the reducing of apoptosis in TINCR-knockdown HCC cells was remarkably reversed with TCPTP silence. Additionally, Δ1-360 TINCR overexpression did not affect HCC cell growth, apoptosis, migration, infiltration, and STAT3 target genes expression. Our data revealed that TINCR directly bound TCPTP and suppressed the dephosphorylation of STAT3, thus promoting STAT3 activation and its downstream target genes in HCC progression and tumorigenicity.HighlightsLncRNA TINCR interacted with protein TCPTPLncRNA TINCR maintained STAT3 phosphorylationLncRNA TINCR affected STAT3 signaling in HCCAbbreviations:lncRNAs: long non-coding RNAs; TINCR: terminal differentiation-induced lncRNA; TCPTP: T cell protein tyrosine phosphatase; siRNA: small-interfering RNA; HCC: hepatocellular carcinoma; nt: nucleotide; LC-MS/MS: Liquid Chromatography - Tandem Mass Spectrometry; RIP: RNA immunoprecipitation; ANOVA: analysis of variance; EdU: 5-ethynyl-2'-deoxyuridine; real-time PCR: real-time polymerase chain reaction; CCK-8: cell counting kit-8; aa: amino acids; STAT3: signal transducer and activator of transcription 3.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genéticaRESUMO
Breast cancer (BC) is the most common tumor in women, and the molecular mechanism underlying its pathogenesis remains unclear. In this study, we aimed to investigate gene modules related to the phenotypes of BC, and identify representative candidate biomarkers for clinical prognosis of BC patients. Using weighted gene co-expression network analysis, we here identified NPY5R as a hub gene in BC. We further found that NPY5R was frequently downregulated in BC tissues compared with adjacent tumor-matched control tissues, due to its aberrant promoter CpG methylation which was confirmed by methylation analysis and treatment with demethylation agent. Higher expression of NPY5R was closely associated with better prognosis for BC patients. Gene set enrichment analysis showed that transcriptome signatures concerning apoptosis and cell cycle were critically enriched in specimens with elevated NPY5R. Ectopic expression of NPY5R significantly curbed breast tumor cell growth, induced cell apoptosis and G2/M arrest. Moreover, NPY5R also promoted the sensitivity of BC cells to doxorubicin. Mechanistically, we found that NPY5R restricted STAT3 signaling pathway activation through interacting with IL6, which may be responsible for the antitumor activity of NPY5R. Collectively, our findings indicate that NPY5R functions as a tumor suppressor but was frequently downregulated in BC.