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The high theoretical specific energy and environmental friendliness of zinc-air batteries (ZABs) have garnered significant attention. However, the practical application of ZABs requires overcoming the sluggish kinetics associated with oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Herein, 3D self-supported nitrogen-doped carbon nanotubes (N-CNTs) arrays encapsulated by CoNi nanoparticles on carbon fiber cloth (CoNi@N-CNTs/CFC) are synthesized as bifunctional catalysts for OER and ORR. The 3D interconnected N-CNTs arrays not only improve the electrical conductivity, the permeation and gas escape capabilities of the electrode, but also enhance the corrosion resistance of CoNi metals. DFT calculations reveal that the co-existence of Co and Ni synergistically reduces the energy barrier for OOH conversion to OH, thereby optimizing the Gibbs free energy of the catalysts. Additionally, analysis of the change in energy barrier during the rate-determining step suggests that the primary catalytic active center is Ni site for OER. As a result, CoNi@N-CNTs/CFC exhibits superior catalytic activity with an overpotential of 240 mV at 10 mA cm-2 toward OER, and the onset potential of 0.92 V for ORR. Moreover, utilization of CoNi@N-CNTs/CFC in liquid and solid-state ZABs exhibited exceptional stability, manifesting a consistent cycling operation lasting for 100 and 15 h, respectively.
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OBJECTIVE: To investigate the impact of urinary iodine concentration (UIC) and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of differentiated thyroid cancer (DTC) patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors. METHODS: A total of 213 DTC patients received initial radioiodine therapy from June 2022 to September 2023. Demographic data and UIC were collected before and after therapy. Thyrotropin, thyroglobulin (Tg), and thyroglobulin antibody levels were assessed. Iodine uptake rate was measured, and therapeutic efficacy was evaluated 6 months post-therapy. Statistical tests were used for data comparison, and logistic regression analysis for response factors. RESULTS: Post-therapy UIC and pre-post UIC difference were significantly correlated with Tg levels but not with reaching excellent response (ER) indicated by suppression of Tg levels below 0.2 ug/L. Ps-Tg levels related to therapeutic efficacy, while UIC did not correlate with outcomes. ROC curve analysis found optimal ps-Tg cut-off points for the low-intermediate and high-risk groups classified by primary tumor size, invasion, metastasis, and pathological type. CONCLUSION: Post-treatment UIC and pre-post UIC difference correlate with ps-Tg levels. Ps-Tg levels are an associated factor for DTC, but UIC changes, despite correlation with ps-Tg, are not significantly related to outcomes and cannot be used as a prognostic factor.
ObjectiveTo investigate the impact of urinary iodine concentration (UIC) and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of differentiated thyroid cancer (DTC) patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors.Methods213 DTC patients received initial radioiodine therapy from June 2022 to September 2023. Demographic data and UIC were collected before and after therapy. Thyrotropin, thyroglobulin, and thyroglobulin antibody levels were assessed. Iodine uptake rate was measured, and therapeutic efficacy evaluated 6 months post-therapy. Statistical tests were used for data comparison and logistic regression analysis for response factors.ResultsPost-therapy UIC and pre-post UIC difference were significantly correlated with thyroglobulin levels but not with reaching excellent response (ER) where suppression of Tg levels below 0.2ug/l. Ps-Tg levels related to therapeutic efficacy, while UIC did not correlate with outcomes. ROC curve analysis found optimal ps-Tg cut-off points for low-intermediate and high-risk groupsclassified by primary tumor size, invasion, metastasis, and pathological type.ConclusionPost-treatment UIC and pre-post UIC difference correlate with ps-Tg levels. Ps-Tg levels are an associated factor for DTC, but UIC changes, despite correlation with ps-Tg, are not significantly related to outcomes and cannot be used as a prognostic factor.
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Radioisótopos de Yodo , Yodo , Tiroglobulina , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/orina , Neoplasias de la Tiroides/patología , Radioisótopos de Yodo/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Tiroglobulina/sangre , Adulto , Yodo/orina , Resultado del Tratamiento , Pronóstico , Anciano , Tirotropina/sangreRESUMEN
Background: Rice blast, caused by Magnaporthe oryzae, seriously damages the yield and quality of rice worldwide. Pi-ta is a durable resistance gene that combats M. oryzae carrying AVR-Pita1. However, the distribution of the Pi-ta gene in rice germplasms in Yunnan Province has been inadequately studied. Methods: We analyzed the potential molecular evolution pattern of Pi-ta alleles by examining the diversity in the coding sequence (CDS) among rice varieties. Results: The results revealed that 95% of 405 rice landraces collected from different ecological regions in Yunnan Province carry Pi-ta alleles. We identified 17 nucleotide variation sites in the CDS regions of the Pi-ta gene across 385 rice landraces. These variations led to the identification of 28 Pi-ta haplotypes, encoding 12 novel variants. Among these, 5 Pi-ta haplotypes (62 rice landraces) carried R alleles. The evolutionary cluster and network of the Pi-ta haplotypes suggested that the Pi-ta S alleles were the ancestral alleles, which could potentially evolve into R variants through base substitution. Conclusions: This study suggests that Pi-ta alleles are diverse in the rice landraces in Yunnan, and the Pi-ta sites resistant to blast evolved from the susceptible plants of the rice landraces. These results provide the basis for breeding resistant varieties.
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Evolución Molecular , Haplotipos , Oryza , Proteínas de Plantas , Oryza/genética , Oryza/microbiología , China , Proteínas de Plantas/genética , Alelos , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Resistencia a la Enfermedad/genética , Filogenia , Ascomicetos , Receptores Citoplasmáticos y NuclearesRESUMEN
Radiotherapy is a commonly used method in the treatment of bladder cancers (BC). Radiation-induced immunogenic cell death (ICD) is related to the immune response against cancers and their prognoses. Even though dendritic cells (DC) act as powerful antigen-presenting cells in the body, their precise role in this ICD process remains unclear. Accordingly, an in vitro study was undertaken to ascertain whether high-dose radiation-induced ICD of BC cells could regulate the immune response of DC. The results indicated that high-dose radiation treatments of BC cells significantly increased their levels of apoptosis, blocked their cell cycle in the G2/M phase, increased their expression of ICD-related proteins, and upregulated their secretion of CCL5 and CCL21 which control the directed migration of DC. It was also noted that expression of CD80, CD86, CCR5, and CCR7 on DC was upregulated in the medium containing the irradiated cells. In conclusion, the present findings illustrate that high-dose radiation can induce the occurrence of ICD within BC cells, concomitantly resulting in the activation of DC. Such findings could be of great significance in increasing the understanding how radiotherapy of BC may work to bring about reductions in cell activity and how these processes in turn lead to immunoregulation of the function of DC.
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Apoptosis , Células Dendríticas , Muerte Celular Inmunogénica , Neoplasias de la Vejiga Urinaria , Células Dendríticas/inmunología , Células Dendríticas/efectos de la radiación , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/patología , Humanos , Línea Celular Tumoral , Apoptosis/efectos de la radiación , Muerte Celular Inmunogénica/efectos de la radiación , Quimiocina CCL21/metabolismo , Receptores CCR7/metabolismo , Quimiocina CCL5/metabolismo , Receptores CCR5/metabolismo , Antígeno B7-2/metabolismo , Movimiento Celular/efectos de la radiación , Antígeno B7-1/metabolismo , Relación Dosis-Respuesta en la RadiaciónRESUMEN
Oral delivery of proteins faces challenges due to the harsh conditions of the gastrointestinal (GI) tract, including gastric acid and intestinal enzyme degradation. Permeation enhancers are limited in their ability to deliver proteins with high molecular weight and can potentially cause toxicity by opening tight junctions. To overcome these challenges, we propose the use of montmorillonite (MMT) as an adjuvant that possesses both inflammation-oriented abilities and the ability to regulate gut microbiota. This adjuvant can be used as a universal protein oral delivery technology by fusing with advantageous binding amino acid sequences. We demonstrated that anti-TNF-α nanobody (VII) can be intercalated into the MMT interlayer space. The carboxylate groups (-COOH) of aspartic acid (D) and glutamic acid (E) interact with the MMT surface through electrostatic interactions with sodium ions (Na+). The amino groups (NH2) of asparagine (N) and glutamine (Q) are primarily attracted to the MMT layers through hydrogen bonding with oxygen atoms on the surface. This binding mechanism protects VII from degradation and ensures its release in the intestinal tract, as well as retaining biological activity, leading to significantly enhanced therapeutic effects on colitis. Furthermore, VII@MMT increases the abundance of short-chain fatty acids (SCFAs)-producing strains, including Clostridia, Prevotellaceae, Alloprevotella, Oscillospiraceae, Clostridia_vadinBB60_group, and Ruminococcaceae, therefore enhance the production of SCFAs and butyrate, inducing regulatory T cells (Tregs) production to modulate local and systemic immune homeostasis. Overall, the MMT adjuvant provides a promising universal strategy for protein oral delivery by rational designed protein.
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Bentonita , Microbioma Gastrointestinal , Factor de Necrosis Tumoral alfa , Bentonita/química , Animales , Administración Oral , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Microbioma Gastrointestinal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Anticuerpos de Dominio Único/administración & dosificación , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/farmacología , Humanos , Inflamación/tratamiento farmacológico , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacologíaRESUMEN
OBJECTIVE: This study assessed the diagnostic value of microRNA-200 (miR-200) expression in peripheral blood-derived extracellular vesicles (EVs) in early-stage non-small cell lung cancer (NSCLC). METHODS: This study retrospectively analyzed 100 healthy volunteers (the control group) receiving physical examinations, 168 early-stage NSCLC patients (the NSCLC group), and 128 patients with benign lung nodules (the benign group). The basic and clinical data of participants were obtained, including age, sex, smoking history, carbohydrate antigen 242 (CA242), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), forced expiratory volume in 1 s, maximal voluntary ventilation, forced vital capacity, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and miR-200 expression. The correlation of miR-200 expression in peripheral blood-derived EVs with CA242, CEA, and CA199 was analyzed, and the diagnostic value of peripheral blood-derived EV miR-200 for early-stage NSCLC was assessed. The risk factors of early-stage NSCLC development were also determined. RESULTS: Age, the percentage of patients with smoking history, CA242, CEA, CA199, IL-6, and TNF-α levels, and miR-200 expression in peripheral blood-derived EVs were significantly higher in the NSCLC group than in the benign and control groups. Lung disease patients with high miR-200 expression in peripheral blood-derived EVs comprised a higher percentage of patients with smoking history and mixed lesions and had higher CA242, CEA, CA199, and TNF-α levels than those with low miR-200 expression in peripheral blood-derived EVs. In lung diseases, miR-200 expression in peripheral blood-derived EVs was significantly and positively correlated with CA242, CEA, and CA199. Peripheral blood-derived EV miR-200 combined with CA242, CEA and CA199 had higher diagnostic value (area under the curve = 0.942) than single detection, along with higher specificity, and high expression of peripheral blood-derived EV miR-200 was an independent risk factor for early-stage NSCLC. CONCLUSION: Peripheral blood-derived EV miR-200 expression in patients with lung diseases is closely correlated with CA242, CEA, and CA199, and high expression of peripheral blood-derived EV miR-200 is an independent risk factor for early-stage NSCLC and is of high clinical diagnostic value for early-stage NSCLC.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Vesículas Extracelulares , Neoplasias Pulmonares , MicroARNs , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/sangre , Femenino , Masculino , Persona de Mediana Edad , MicroARNs/sangre , MicroARNs/genética , Vesículas Extracelulares/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Estudios Retrospectivos , Biomarcadores de Tumor/sangre , Anciano , Adulto , Estadificación de Neoplasias , Detección Precoz del Cáncer/métodos , Antígeno Carcinoembrionario/sangreRESUMEN
Cotton is a widely planted commercial crop in the world. Enhancing fiber yield and quality is a long-term goal for cotton breeders. Our previous work has demonstrated that fine promotion of auxin biosynthesis in ovule epidermis, by overexpressing FBP7pro::iaaM, has a significant improvement on lint yield and fiber fineness. Lately, transgenic cottons overexpressing GhROP6 variants modify mature fiber length by controlling GhPIN3a-mediated polar auxin transport in ovules. Here, this study showed that all these GhROP6-related cottons displayed unsatisfactory agronomic performance in field conditions. Yet extra auxin supply could promote their fiber development, suggesting inadequate auxin supply in the ovules. Thus, these cottons were integrated with enhanced auxin synthesis by crossing with FBP7pro::iaaM cotton. All the transgene-stacked cottons exhibited synergetic effects on cotton yield (seedcotton yield, lint yield, and lint percentage) and quality (length, strength, and micronaire). Notably, comparing to the FBP7pro::iaaM background, the transgene-stacked cotton co-expressing FBP7pro::iaaM and CA-ghrop6 (constitutively active GhROP6) exhibited a 12.6% increase in seedcotton yield and a 19.0% increase in lint yield over a three-year field trial, and simultaneously resulted in further improvement on fiber length, strength, and micronaire. Collectively, our data provide a potential strategy for genetic improvement on cotton fiber yield and quality. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01500-w.
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Scientific risk assessment of exogenous and endogenous toxic substances in traditional Chinese medicine (TCM) is of great significance. The present review comprises a comprehensive summary of progress in the health risk assessment of harmful exogenous substances in TCMs. Such substances include heavy metals, pesticide residues, biotoxins, and endogenous toxic components involving pyrrolizidine alkaloids. The review also discusses the strengths and weaknesses of various bioaccessibility and bioavailability models, and their applications in risk assessment. Future avenues of risk assessment research are highlighted, including further exploration of risk assessment parameters, innovation of bioaccessibility and bioavailability techniques, enhancement of probabilistic risk assessment combined with bioavailability, improvement of cumulative risk assessment strategies, and formulation of strategies for reducing relative bioavailability (RBA) values in TCMs. Such efforts represent an attempt to develop a risk assessment system that is capable of evaluating the exogenous and endogenous toxic substances in TCMs to ensure its safe use in clinics, and to promote the sustainable development of the TCM industry.
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Disponibilidad Biológica , Medicamentos Herbarios Chinos , Medicina Tradicional China , Medición de Riesgo , Humanos , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/toxicidad , Medicamentos Herbarios Chinos/efectos adversos , Animales , Residuos de Plaguicidas/farmacocinética , Residuos de Plaguicidas/toxicidad , Residuos de Plaguicidas/análisis , Metales PesadosRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC), theseventh most common cancer worldwide, is characterized by a high mortality rate, advanced diagnosis, and susceptibility to extrahepatic metastasis. Numerous studies have shown that DNA methylation is a crucial factor in epigenetic modifications and regulation of carcinogenesis. METHODS: HCC patient data were sourced from the TCGA dataset as a training set, while GSE116174 was used as an external validation set for verification. Differential methylation and expression analyses were performed on HCC samples with and without extrahepatic metastasis. In the intersecting genes, the relationship between methylation and expression levels of the intersecting genes was analyzed. Genes with a correlation coefficient≥|0.30| and P<0.05 were identified as methylation driver genes. Cox regression analysis was conducted to identify genes associated with HCC prognosis and establish a risk score. Subsequently, a prognostic model was established and validated using Cox regression analysis incorporating the risk score and other clinical factors. Using immunohistochemistry to evaluate the expression of DHX58 and EIF5A2 in HCC tissues with and without extrahepatic metastasis. Immunoinfiltration analysis was performed on the HCC samples using CIBERSORT. RESULTS: Our research identified eight methylation driver genes for HCC extrahepatic metastasis, of which two genes (DHX58 and EIF5A2) were associated with HCC patient prognosis. And the study further constructed and validated the risk score and prognostic model. Immunoinfiltration analysis showed that M0 macrophage abundance was correlated with the prognosis of HCC patients. Immunohistochemistry revealed differences in DHX58 and EIF5A2 expression between HCC tissues with and without extrahepatic metastasis, consistent with our bioinformatics findings.
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Exopolysaccharides (EPSs), which show excellent biological activities, like anti-tumor, immune regulation, and anti-oxidation activities, have gained widespread attention. In this study, an EPS-producing Saccharomyces cerevisiae HD-01 was identified based on 18S rDNA sequence analysis and an API 20C test. The purified HD-01 EPS was obtained by gel filtration chromatography. High-performance liquid chromatography (HPLC), gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT-IR), and nuclear magnetic resonance (NMR) revealed that it was a heteropolysaccharide composed of α-1 (38.3%), α-1, 2 (17.5%), α-1, 6 (14.8%)-linked mannose and α-1, 2, 3, 6 (24.3%), α-1 (3.3%), ß-1, 4 (1.8%)-linked glucose. Chemical composition and elemental analysis indicated the existence of sulfation modifications. A scanning electron microscope (SEM) and an atomic force microscope (AFM) revealed that it exhibited a flaky structure with thorn-like protrusions on the three-dimensional surface. X-ray diffraction (XRD) revealed that it was an amorphous non-crystalline substance. HD-01 EPS had great thermostability; probiotic properties; strong antioxidant properties to DPPH, ABTS, and hydroxyl; and good reducing power. The MTT, NO, and neutral red assays demonstrated that it had a great immunomodulatory effect on macrophages RAW264.7. All results suggested that the HD-01 EPS had the potential to be applied in the food and pharmaceutical fields.
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Most two-dimensional (2D) materials experimentally studied so far have hexagons as their building blocks. Only a few exceptions, such as PdSe2, are lower in energy in pentagonal phases and exhibit pentagons as building blocks. Although theory has predicted a large number of pentagonal 2D materials, many of these are metastable and their experimental realization is difficult. Here we report the successful synthesis of a metastable pentagonal 2D material, monolayer pentagonal PdTe2, by symmetry-driven epitaxy. Scanning tunnelling microscopy and complementary spectroscopy measurements are used to characterize this material, which demonstrates well-ordered low-symmetry atomic arrangements and is stabilized by lattice matching with the underlying Pd(100) substrate. Theoretical calculations, along with angle-resolved photoemission spectroscopy, reveal monolayer pentagonal PdTe2 to be a semiconductor with an indirect bandgap of 1.05 eV. Our work opens an avenue for the synthesis of pentagon-based 2D materials and gives opportunities to explore their applications such as multifunctional nanoelectronics.
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The Yangtze River Delta (YRD) experienced record-breaking heat in the summer of 2022. However, the urban heat pattern and the role of urban expansion over the last two decades in this hot summer have not been explored. Using the advanced mesoscale Weather Research and Forecasting (WRF) model, we reproduced the fine spatial features and investigated the urban heat island (UHI) and dry island (UDI) effects during the two identified heatwaves in 2022. We further replace the current (2020) land use with the historical (2001) land use in WRF to evaluate the impacts of urban expansion from 2001 to 2020 on air temperature and moisture. Our finding revealed that the conversion of land use resulted in near-surface warming and drying, with pronounced diurnal variations, especially during the July heatwave. The analysis of surface energy balance demonstrated that the substantial decrease in evapotranspiration (ET) was the primary driver of daytime warming, elevating temperatures by 7 °C (July heatwave) and 2 °C (August heatwave). This ET reduction also led to the strong daytime coupling of warming and drying effects over new urban areas. At night, the release of stored heat resulted in the temperature increase of 2 °C (1 °C) during July (August) heatwave, highlighting the nighttime as a critical period for heightened thermal risk. Additionally, urban expansion at the periphery contributed modestly to the warming of urban cores, exacerbating conditions in an already hot environment. This study enhances understanding of the impacts of urban expansion on air temperature and humidity during extreme heatwaves, thereby supporting targeted adaptation and mitigation for extreme events within large cities.
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OBJECTIVE: To investigate whether lymph node (LN) yield influences clinical outcomes for pediatric patients with laterocervical lymph node metastasis (N1b) from papillary thyroid cancer (PTC). METHODS: Conducted from January 1, 2008, to December 31, 2022, this was a cohort study of pediatric patients (aged ≤ 18 years) with N1b PTC who underwent total thyroidectomy and therapeutic LN dissection in the central and lateral compartments at 3 hospitals in southwest China in 2008-2021, with follow-up until 2022. Patients with distant metastasis were excluded. Univariate and multivariate Cox proportional hazards regression analyses were used to identify factors associated with persistent/recurrent diseases. RESULTS: A total of 102 pediatric patients (median [range] age, 16 [6-18] years) were analyzed: 36 patients (35 %) with T1; 27 patients (26 %), T2; 18 patients (18 %), T3; and 21 patients (21 %), T4. During a median follow-up of 50 months (range, 12-154 months), persistent diseases occurred in 40 (39 %) patients. Receiver operating characteristic analysis identified LN yield cut-off (<42 LNs) to predict persistent diseases. Multivariate analysis revealed that a less-extensive lymphadenectomy (<42 LNs) was an independent risk factor for persistent diseases (hazard ratio, 2.4; 95 % confidence intervals, 1.09-5.29; P=.029). CONCLUSIONS: Our study highlights that a higher LN yield may favorably influence prognosis in pediatric patients with N1b PTC.
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Ganglios Linfáticos , Metástasis Linfática , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Masculino , Femenino , Adolescente , Niño , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/cirugía , Pronóstico , Ganglios Linfáticos/patología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Escisión del Ganglio Linfático , TiroidectomíaRESUMEN
BACKGROUND: Post-burn anxiety and depression affect considerably the quality of life and recovery of patients; however, limited research has demonstrated risk factors associated with the development of these conditions. AIM: To predict the risk of developing post-burn anxiety and depression in patients with non-mild burns using a nomogram model. METHODS: We enrolled 675 patients with burns who were admitted to The Second Affiliated Hospital, Hengyang Medical School, University of South China between January 2019 and January 2023 and met the inclusion criteria. These patients were randomly divided into development (n = 450) and validation (n = 225) sets in a 2:1 ratio. Univariate and multivariate logistic regression analyses were conducted to identify the risk factors associated with post-burn anxiety and depression diagnoses, and a nomogram model was constructed. RESULTS: Female sex, age < 33 years, unmarried status, burn area ≥ 30%, and burns on the head, face, and neck were independent risk factors for developing post-burn anxiety and depression in patients with non-mild burns. The nomogram model demonstrated predictive accuracies of 0.937 and 0.984 for anxiety and 0.884 and 0.923 for depression in the development and validation sets, respectively, and good predictive performance. Calibration and decision curve analyses confirmed the clinical utility of the nomogram. CONCLUSION: The nomogram model predicted the risk of post-burn anxiety and depression in patients with non-mild burns, facilitating the early identification of high-risk patients for intervention and treatment.
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Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.
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Neoplasias Encefálicas , Glioblastoma , Receptores Inmunológicos , Proteínas Roundabout , Animales , Femenino , Humanos , Ratones , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/inmunología , Inmunoterapia Adoptiva/métodos , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Proteínas Roundabout/antagonistas & inhibidores , Transducción de Señal , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The escalating issue of plastic waste generation has prompted the search for an effective solution to address these challenges. In this study, we present a novel plasma-enabled strategy for the rapid breakdown of various types of plastic wastes, including mixtures, into high-value carbon nanomaterials and hydrogen. The H2 yield and selectivity achieved through the implemented catalyst-free plasma-enabled strategy are 14.2 and 5.9â times higher, respectively, compared to those obtained with conventional thermal pyrolysis under similar conditions. It is noteworthy that this catalyst-free plasma alone approach yields a significantly higher energy yield of H2 (gH2/kWh) compared to other pyrolysis processes. By coupling plasma pyrolysis with thermal catalytic process, employing of 1â wt . % M/CeO2 (M=Fe, Co, and Ni) atomically dispersed catalysts can further enhance hydrogen production. Specifically, the 1â wt . % Co/CeO2 catalyst demonstrated excellent catalytic performance throughout the 10â cycles of plastic waste decomposition, achieving the highest H2 yield of 46.7â mmol/gplastic (equivalent to 64.4 % of theoretical H2 production) and nearly 100 % hydrogen atom recovery efficiency at the 7th cycle. Notably, the H2 yield achieved over the atomically dispersed Fe on CeO2 surface (1â wt . % Fe/CeO2) in the integrated plasma-thermal catalytic process is comparable to that obtained with Fe particles on CeO2 surface (10â wt . % Fe/CeO2). This outcome, demonstrated with single-atom catalysts, offers a promising avenue for cost-effective and efficient chemical plastic recycling. Through a combination of experimental and computational efforts, we have provided an in-depth understanding of the catalytic mechanisms of the investigated single atom catalysts in the developed plasma-enabled process. This innovative and straightforward approach provides a promising and expedient strategy for continuously converting diverse plastic waste streams, including mixed and contaminated sources, into high-value products conducive to a circular plastic economy.
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Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post-transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post-transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post-transcriptional control as actionable targets for precision therapy of AML.
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Near-infrared (NIR) light has characteristics of invisibility to human eyes, less background interference, low light scattering, and strong cell penetration. Therefore, NIR luminescent materials have significant applications in imaging, sensing, energy, information storage and display. The development of NIR luminescent materials thus has emerged as a highly dynamic area of research in the realm of contemporary materials. To date, NIR luminescent materials are roughly divided into inorganic materials and organic materials. Compared with inorganic materials, organic NIR luminescent materials have become a hot research topic in recent years due to their rich sources, easy control of structure, simple preparation process, low cost, and good film-forming properties. Among them, iridium(III) [Ir(III)] complexes exhibit excellent properties such as thermal stability, simple synthesis, easy color modulation, short excited state lifetimes, and high brightness, thus becoming one of the ideal luminescent material systems for preparing high-quality organic light-emitting diodes. Therefore, how to obtain Ir(III) complexes with NIR emission and high efficiency through molecular design is a necessary and promising research topic. This work reviews the research progress of representative NIR Ir(III) complexes bearing isoquinoline-, phenazine-, and phthalazine-based ligands reported in recent years and introduces the design strategies and electroluminescent performances of NIR Ir(III) complexes.
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Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.