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Magnetic solid-phase extraction (MSPE) technology for tetracycline (TCC) was developed by employing the novel and pre-designed Fe3O4-COOH@hydrogen-bonded organic frameworks (HOFs) adsorbents in complex food samples. The HOF shell was grown onto the Fe3O4-COOH core by in-situ self-assembled method. The excellent MSPE performances with less solvent, less adsorbent and time consumption were derived from the hydrogen bonding, π-π and hydrophobic interactions between HOF shell and TCC. Combined with HPLC analysis, Fe3O4@ HOFs adsorbent reduced matrix effects and the established MSPE-HPLC method for TCC gave the linearity of 0.001-6 µg mL-1 with the limit of detection 0.0003 µg mL-1. The recoveries in pure milk, canned yellow peach and carrot were 82.4-103.7 %. The method provided a simple, efficient and dependable alternative to monitor trace TCC antibiotics in food or environmental samples.
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Novel magnetic covalent organic frameworks (COFs) were prepared by one-pot synthetic strategy and employed as an efficient adsorbent for magnetic solid-phase extraction (MSPE) of naphthaleneacetic acid (NAA) in food samples. Depending on the predesigned the hydrogen bonding, π-π and hydrophobic interactions of magnetic COFs, the efficient and selective extraction process for NAA was achieved within 15 min. The magnetic COFs adsorbent combined with HPLC-UV was devoted to develop a novel quantitative method for NAA in complex food. The method afforded good coefficient in range of 0.002-10.0 µg mL-1 and low limit of detection was 0.0006 µg mL-1. And the newly established method afforded less adsorbent consumption, wider linearity and lower LODs than the reported analytical methods. Ultimately, the method was successfully applied to determine NAA in fresh pear, tomato and peach juice. The magnetic COFs based MSPE coupled with HPLC-UV method provided a simple, efficient and dependable alternative to monitor trace NAA in food samples.
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Límite de Detección , Estructuras Metalorgánicas , Ácidos Naftalenoacéticos , Extracción en Fase Sólida , Extracción en Fase Sólida/métodos , Cromatografía Líquida de Alta Presión/métodos , Ácidos Naftalenoacéticos/análisis , Ácidos Naftalenoacéticos/química , Estructuras Metalorgánicas/química , Adsorción , Contaminación de Alimentos/análisis , Solanum lycopersicum/química , Jugos de Frutas y Vegetales/análisisRESUMEN
The primary inhibitory targets of phenyllactic acid (PLA, including D-PLA and L-PLA) on Mucor were investigated using Mucor racemosus LD3.0026 isolated from naturally spoiled cherry, as an indicator fungi. The results demonstrated that the minimum inhibitory concentration (MIC) of PLA against Mucor was 12.5 mmol·L-1. Results showed that the growing cells at the tip of the Mucor were not visibly deformed, and there was no damage to the cell wall following PLA treatment; however, PLA damaged the cell membrane and internal structure. The results of isobaric tags for relative and absolute quantification (iTRAQ) indicated that the Mucor mitochondrial respiratory chain may be the target of PLA, potentially inhibiting the energy supply of Mucor. These results indicate that the antifungal mechanism of PLA against mold is independent of its molecular configuration. The growth of Mucor is suppressed by PLA, which destroys the organelle structure in the mycelium and inhibits energy metabolism.
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Antifúngicos , Mucor , Proteómica , Mucor/metabolismo , Mucor/crecimiento & desarrollo , Mucor/química , Mucor/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Pruebas de Sensibilidad Microbiana , Lactatos/farmacología , Lactatos/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/químicaRESUMEN
BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. TRIAL REGISTRATION: ChiCTR2000031608.
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Antineoplásicos , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Neoplasias de Cabeza y Cuello , Melanoma , Piperidinas , Piridinas , Pirimidinas , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Antineoplásicos/efectos adversos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Amplificación de Genes , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Resultado del Tratamiento , Piperidinas/efectos adversos , Piridinas/efectos adversos , Pirimidinas/efectos adversosRESUMEN
Introduction: Traditional modified atmosphere packaging (MAP) cannot meet the preservation requirements of winter jujube, and the high respiration rate characteristics of winter jujube will produce an atmosphere component with high CO2 concentration in traditional MAP. Micro-perforated MAP is suitable for the preservation of winter jujube due to its high permeability, which can effectively remove excess CO2 and supply O2. In this study, a microporous film preservation system that can be quickly applied to winter jujube was developed, namely PMP-MAP (precise micro-perforated modified atmosphere packaging). An experiment was designed to store winter jujube in PMP-MAP at 20°C and 2°C, respectively. The quality, aroma and antioxidant capacity, etc. of winter jujube at the storage time were determined. Methods: In this study, the optimal micropore area required for microporous film packaging at different temperatures is first determined. To ensure the best perforation effect, the effects of various factors on perforation efficiency were studied. The gas composition within the package was predicted using the gas prediction equation to ensure that the gas composition of the perforated package achieved the desired target. Finally, storage experiments were designed to determine the quality index of winter jujube, including firmness, total soluble solids, titratable acid, reddening, and decay incidence. In addition, sensory evaluation, aroma and antioxidant capacity were also determined. Finally, the preservation effect of PMP-MAP for winter jujube was evaluated by combining the above indicators. Results and discussion: At the end of storage, PMP-MAP reduced the respiration rate of winter jujube, which contributed to the preservation of high total soluble solids and titratable acid levels, and delayed the reddening and decay rate of winter jujube. In addition, PMP-MAP maintained the antioxidant capacity and flavor of winter jujube while inhibiting the occurrence of alcoholic fermentation and off-flavors. This can be attributed to the effective gas exchange facilitated by PMP-MAP, thereby preventing anaerobic stress and quality degradation. Therefore, the PMP-MAP approach is an efficient method for the storage of winter jujube.
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To reduce food-borne bacterial infection caused by food spoilage, developing highly efficient food packing film is still an urgent need for food preservation. Herein, microwave-assisted antibacterial nanocomposite films CaO2@PVP/EA/CMC-Na (CP/EC) were synthesized using waste eggshell as precursor, egg albumen (EA) and sodium carboxymethylcellulose (CMCNa) as matrix by casting method. The size of CaO2@PVP (CP) nanoparticles with monodisperse spherical structures was 100-240 nm. When microwave and CP nanoparticles (0.05 mg/mL) were treated for 5 min, the mortality of E. coli and S. aureus could reach >97 %. Under microwave irradiation (6 min), the bactericidal rate of 2.5 % CP/EC film against E. coli and S. aureus reached 98.6 % and 97.2 %, respectively. After adding CP nanoparticles, the highest tensile strength (TS) and elongation at break (EB) of CP/EC film reached 19.59 MPa and 583.43 %, respectively. At 18 °C, the proliferation of bacterial colonies on meat can be significantly inhibited by 2.5 % CP/EC film. Detailed characterization showed that the excellent meat preservation activity was due to the synergistic effect of dynamic effect generated by ROS and thermal effect of microwave. This study provides a promising approach for the packaging application of polysaccharide- and protein-based biomass nanocomposite antibacterial edible films.
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Antibacterianos , Películas Comestibles , Escherichia coli , Conservación de Alimentos , Carne , Microondas , Polisacáridos , Staphylococcus aureus , Polisacáridos/química , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Conservación de Alimentos/métodos , Carne/microbiología , Antibacterianos/farmacología , Antibacterianos/química , Staphylococcus aureus/efectos de los fármacos , Embalaje de Alimentos/métodos , Animales , Nanocompuestos/química , Carboximetilcelulosa de Sodio/química , Nanopartículas/química , Proteínas/química , Resistencia a la TracciónRESUMEN
The GSK3/SHAGGY-like kinase plays critical roles in plant development and response to stress, but its specific function remains largely unknown in wheat (Triticum aestivum L.). In this study, we investigated the function of TaGSK3, a GSK3/SHAGGY-like kinase, in wheat development and response to stress. Our findings demonstrated that TaGSK3 mutants had significant effects on wheat seedling development and brassinosteroid (BR) signalling. Quadruple and quintuple mutants showed amplified BR signalling, promoting seedling development, while a sextuple mutant displayed severe developmental defects but still responded to exogenous BR signals, indicating redundancy and non-BR-related functions of TaGSK3. A gain-of-function mutation in TaGSK3-3D disrupted BR signalling, resulting in compact and dwarf plant architecture. Notably, this mutation conferred significant drought and heat stress resistance of wheat, and enhanced heat tolerance independent of BR signalling, unlike knock-down mutants. Further research revealed that this mutation maintains a higher relative water content by regulating stomatal-mediated water loss and maintains a lower ROS level to reduces cell damage, enabling better growth under stress. Our study provides comprehensive insights into the role of TaGSK3 in wheat development, stress response, and BR signal transduction, offering potential for modifying TaGSK3 to improve agronomic traits and enhance stress resistance in wheat.
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Brasinoesteroides , Proteínas de Plantas , Transducción de Señal , Estrés Fisiológico , Triticum , Triticum/genética , Triticum/fisiología , Triticum/crecimiento & desarrollo , Brasinoesteroides/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Sequías , Regulación de la Expresión Génica de las Plantas , Plantones/crecimiento & desarrollo , Plantones/fisiología , Plantones/genética , Adaptación Fisiológica/genética , Mutación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.
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Ácido Aminolevulínico , Mitocondrias , Neoplasias de la Boca , Fotoquimioterapia , Fármacos Fotosensibilizantes , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Fotoquimioterapia/métodos , Humanos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Animales , Línea Celular Tumoral , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Ácido Aminolevulínico/química , Ácido Aminolevulínico/farmacología , Ratones , Dióxido de Silicio/química , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Sistemas de Liberación de Medicamentos/métodos , Ratones DesnudosRESUMEN
Both the roots and leaves of American ginseng contain ginsenosides and polyphenols. The impact of thermal processing on enhancing the biological activities of the root by altering its component composition has been widely reported. However, the effects of far-infrared irradiation (FIR), an efficient heat treatment method, on the bioactive components of the leaves remain to be elucidated. In the present study, we investigated the effects of FIR heat treatment between 160 and 200 °C on the deglycosylation and dehydration rates of the bioactive components in American ginseng leaves. As the temperature was increased, the amounts of common ginsenosides decreased while those of rare ginsenosides increased. After FIR heat treatment of American ginseng leaves at an optimal 190 °C, the highest total polyphenolic content and kaempferol content were detected, the antioxidant activity was significantly enhanced, and the amounts of the rare ginsenosides F4, Rg6, Rh4, Rk3, Rk1, Rg3, and Rg5 were 41, 5, 37, 64, 222, 17, and 266 times higher than those in untreated leaves, respectively. Moreover, the radical scavenging rates for 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) and the reducing power of the treated leaf extracts were 2.17, 1.86, and 1.77 times higher, respectively. Hence, FIR heat treatment at 190 °C is an efficient method for producing beneficial bioactive components from American ginseng leaves.
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To investigate various population biological parameters of Xenocypris argentea in the lower reaches of the Tangwang River (China), a comprehensive study was conducted for the first time. A total of 1,003 samples were collected from April to November 2022. The collected samples revealed that female X. argentea had total lengths ranging from 12.4 cm to 25.7 cm (weighing 15.86 g to 159.55 g), and male X. argentea had total lengths ranging from 10.8 cm to 23.9 cm (weighing 9.27 g to 121.06 g). The age of the samples was determined using otolith analysis, indicating that the ages ranged from 1 to 5 years old in both females and males. The length-weight relationships were further analyzed, uncovering the allometric growth index (b) was 3.1296 for females, indicating a positive allometric growth pattern. Differently, males exhibited a b value of 3.0274, suggesting an isometric growth pattern. Furthermore, the von Bertalanffy growth formula provided insights into the growth characteristics of X. argentea, revealing an asymptotic total length (L∞) of 36.096 cm and a growth coefficient (K) of 0.121. The analysis of the gonadal somatic index (GSI) and ovarian development period indicated that the spawning period occurred from April to July, with peak spawning in June. The study also explored fecundity-related traits, finding that individual absolute fecundity (FA) ranged from 11,364 eggs to 56,377 eggs, while eviscerated body weight relative fecundity (FW) ranged from 209 eggs/g to 823 eggs/g. The exploitation rate (E) for X. argentea was calculated as 0.574, suggesting that the population of X. argentea has been overexploited. By revealing previously unknown data on the key life history traits of X. argentea, this study has provided valuable insights that are crucial for the development of conservation strategies and policies.
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Cipriniformes , Ríos , Animales , Femenino , Masculino , Reproducción , Fertilidad , GónadasRESUMEN
Food safety of aquatic products has attracted considerable attention worldwide. Although a series of conventional bioassays and instrumental methods have been developed for the detection of pathogenic bacteria, heavy metal residues, marine toxins, and biogenic amines during the production and storage of fish, shrimp, crabs et al., the nanotechnology-based analyses still have their advantages and are promising since they are cost-efficient, highly sensitive and selective, easy to conduct, facial design, often require no sophisticated instruments but with excellent detection performance. This review aims to summarize the advances of various biosensing strategies for bacteria, metal ions, and small molecule contaminants in aquatic products during the last five years, The review highlights the development in nanotechnologies applied for biorecognition process, signal transduction and amplification methods in each novel approach, the nuclease-mediated DNA amplification, nanomaterials (noble metal nanoparticle, metal-organic frameworks, carbon dots), lateral flow-based biosensor, surface-enhanced Raman scattering, microfluidic chip, and molecular imprinting technologies were especially emphasized. Moreover, this study provides a view of current accomplishments, challenges, and future development directions of nanotechnology in aquatic product safety evaluation.
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Técnicas Biosensibles , Nanoestructuras , Animales , Nanotecnología/métodos , Nanoestructuras/química , Inocuidad de los Alimentos/métodos , Técnicas Biosensibles/métodos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Smoked duck is a popular meat product in China. The aroma profile and key aroma compounds in smoked ducks were elucidated using solvent-assisted flavor evaporation-gas chromatography-olfactometry-mass spectrometry (SAFE-GC-O-MS), odor activity values (OAVs), aroma recombination and omission experiments, and sensory evaluation. The results indicated that the predominant aroma profiles of rice-, tea oil- and sugarcane-smoked ducks all contained strong smoky, roasty, fatty, meaty, and grassy aromas. A total of 31 aroma compounds were identified as important odorants by OAVs, including 8 aldehydes, 6 pyrazines, 5 phenols, and 2 sulfur compounds. The aroma recombination and omission experiments confirmed that 13 odorants were key aroma compounds in smoked ducks. Of these odorants, 2-methoxyphenol, 4-methylphenol, 5-ethyl-2,3-dimethylpyrazine, methional, 2-methyl-3-furanthiol, (E, E)-2,4-decadienal, 1-octen-3-ol, and anethole significantly contributed to the aroma profile of smoked duck flavor (p < 0.01).
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BACKGROUND: T cell engagers (TCEs) have been established as an emerging modality for hematologic malignancies, but solid tumors remain refractory. However, the upregulation of programmed cell death 1 (PD-1) is correlated with T cell dysfunction that confer tumor-mediated immunosuppression. Developing a novel nanobody-based trispecific T cell engager (Nb-TriTE) would be a potential strategy to improve therapeutic efficacy. METHODS: Given the therapeutic potential of nanobodies (Nbs), we first screened Nb targeting fibroblast activation protein (FAP) and successfully generated a Nb-based bispecific T cell engager (Nb-BiTE) targeting FAP. Then, we developed a Nb-TriTE by fusing an anti-PD-1 Nb to the Nb-BiTE. The biological activity and antitumor efficacy of the Nb-TriTE were evaluated in vitro and in both cell line-derived and patient-derived xenograft mouse models. RESULTS: We had for the first time successfully selected a FAP Nb for the generation of novel Nb-BiTE and Nb-TriTE, which showed good binding ability to their targets. Nb-TriTE not only induced robust tumor antigen-specific killing, potent T cell activation and enhanced T cell function in vitro, but also suppressed tumor growth, improved survival and mediated more T cell infiltration than Nb-BiTE in mouse models of different solid tumors without toxicity. CONCLUSIONS: This novel Nb-TriTE provides a promising and universal platform to overcome tumor-mediated immunosuppression and improve patient outcomes in the future.
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Anticuerpos Biespecíficos , Neoplasias , Humanos , Ratones , Animales , Niobio/metabolismo , Neoplasias/terapia , Terapia de Inmunosupresión , Linfocitos T , Tolerancia Inmunológica , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/metabolismoRESUMEN
Mucosal melanoma (MM), an aggressive rare subtype of melanoma, is distinct from cutaneous melanoma and has poor prognoses. We addressed the lack of cell models for MM by establishing 30 organoids of human oral MM (OMM), which retained major histopathological and functional features of parental tumors. Organoid groups derived from chronologically or intratumorally distinct lesions within the same individual displayed heterogeneous genetics, expression profiles, and drug responses, indicating rapid tumor evolution and poor clinical response. Furthermore, transcriptome analysis revealed receptor tyrosine kinases (RTKs) signaling, particularly NGFR, a nerve growth factor receptor, was significantly up-regulated in OMMs and organoids from patients resistant to anti-programmed cell death protein 1 (anti-PD-1) therapy. Combining anti-PD-1 with anlotinib (a phase 2 multitarget RTK inhibitor for OMM) or NGFR knockdown enhanced the effective activity of immune cells in organoid-immune cell coculture systems. Together, our study suggested that OMM organoids serve as faithful models for exploring tumor evolution and immunotherapy combination strategies.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/patología , Perfilación de la Expresión Génica , Inmunoterapia , OrganoidesRESUMEN
Background: Chimeric antigen receptor (CAR) T-cell therapy is practical in treating cancers of hematopoietic origin, but of that in solid tumors compromises efficacy for the loss of the antigen recognized by the CAR. However, dendritic cell (DC)/tumor fusion vaccines present a spectrum of known or unknown tumor antigens to stimulate T cell expansion and enhanced T cell response. Developing a new strategy of enhanced nanobody-based CAR-T (Nb-CAR-T) cells antitumor activity by DC/tumor fusion vaccines stimulation would provide guidance for more effective CAR-T cell therapies. Methods: Considering the therapeutic potential of nanobody (Nb), we first screened EGFRvIII Nb, then constructed and verified the function of EGFRvIII Nb-CAR-T cells in vitro and in vivo. We further combined DC/tumor fusion vaccines to boost EGFRvIII Nb-CAR-T cells antitumor effect, which was evaluated in vitro Nb-CAR-T cell function and in the tumor-bearing xenograft mouse models. Results: We had for the first time successfully selected EGFRvIII Nb for the generation of the novel EGFRvIII Nb-CAR-T cells. Importantly, our results suggested that DC/tumor fusion vaccines stimulate Nb-CAR-T cells response not only in improving T cell proliferation, T cell activation, cytokine secretion and tumor-specific cytotoxicity in vitro, but also significantly reducing tumor burden, prolonging survival and improving Nb-CAR-T cells infiltration. Conclusions: We have innovatively shown that DC/tumor fusion vaccines significantly enhance the efficacy of Nb-CAR-T cells against solid tumors. This new strategy has provided a promising therapeutic platform for promoting the clinical treatment of CAR-T cells therapy.
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Receptores Quiméricos de Antígenos , Humanos , Animales , Ratones , Línea Celular Tumoral , Linfocitos T , Inmunoterapia Adoptiva/métodos , Proliferación Celular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Garnet-type oxide Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) features superior ionic conductivity and good stability toward lithium (Li) metal, but requires high-temperature sintering (≈1200 °C) that induces high fabrication cost, poor mechanical processability, and high interface resistance. Here, a novel high-performance tricomponent composite solid electrolyte (CSE) comprising LLZTO-4LiBH4 /xLi3 BN2 H8 is reported, which is prepared by ball milling the LLZTO-4LiBH4 mixture followed by hand milling with Li3 BN2 H8 . Green pellets fabricated by heating the cold-pressed CSE powders at 120 °C offer ultrafast room-temperature ionic conductivity (≈1.73 × 10-3 S cm-1 at 30 °C) and ultrahigh Li-ion transference number (≈0.9999), which enable the Li|Li symmetrical cells to cycle over 1600 h at 30 °C with only 30 mV of overpotential. Moreover, the Li|CSE|TiS2 full cells deliver 201 mAh g-1 of capacity with long cyclability. These outstanding performances are due to the low open porosity in the electrolyte pellets as well as the high intrinsic ionic conductivity and easy deformability of Li3 BN2 H8 .
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Gastric cancer (GC) is a highly prevalent and aggressive malignancy with a poor prognosis. Recent evidence suggested that metallothionein 1 M (MT1M) may play a critical role in cancer development, progression, and drug resistance; however, its role in GC remains largely unknown. In this study, we investigated the expression and function of MT1M in GC both in vitro and in vivo. We found that MT1M expression was significantly downregulated in GC tissues and cell lines. Decreased expression of MT1M was associated with worse clinical prognosis, particularly in patients treated with 5-fluorouracil. Low expression of MT1M was indicative of poor overall survival (OS, HR 0.56 [95% CI 0.37-0.84], P < 0.005), first progression survival (FP, HR 0.54 [95% CI 0.36-0.79], P < 0.005), and post-progression survival (PPS, HR 0.65 [95% CI 0.45-0.94], P < 0.05). We also demonstrated that overexpression of MT1M inhibited cell proliferation and induced apoptosis in GC cells and in tumor xenografts, and it improved chemosensitivity to 5-fluorouracil. Furthermore, we found that MT1M overexpression could inhibit stem cell characteristics by targeting GLI1 and affecting GLI1 ubiquitination. Collectively, these findings indicated that MT1M may act as a tumor suppressor in GC and could serve as a potential therapeutic target to attenuate stemness and chemotherapy resistance of GC.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Proteínas Hedgehog/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Línea Celular Tumoral , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Metalotioneína/genéticaRESUMEN
Objectives: The role of re-irradiation after salvage surgery for recurrent oral cavity cancer (OCC) is controversial. We evaluated the efficacy and safety of adjuvant toripalimab (PD-1 antibody) in this patient setting. Materials and methods: In this phase II study, patients after salvage surgery with OCC occurring in an area of previously irradiated were enrolled. Patients received toripalimab 240 mg once every 3 weeks for 12 months, or combined with S-1 orally for 4-6 cycles. The primary endpoint was 1-year progression-free survival (PFS). Results: Between April 2019 and May 2021, 20 patients were enrolled. Sixty percent patients had ENE or positive margins, 80% were restaged as stage IV, and 80% were previously treated with chemotherapy. The 1-year PFS and overall survival (OS) were 58.2%, and 93.8%, respectively, for patients with CPS ≥ 1, which was significantly better than those of the real-world reference cohort (p = 0.001 and 0.019). No grade 4-5 toxicities were reported, and only one patient experienced grade 3 immune related adrenal insufficiency and discontinued treatment. The 1-year PFS and OS were significantly different for patients with CPS < 1, CPS 1-19 and CPS ≥ 20 (p = 0.011 and 0.017, respectively). The peripheral blood B cell proportion was also correlated with PD in 6 months (p = 0.044). Conclusion: Adjuvant toripalimab or combine with S-1 after salvage surgery showed improved PFS compared with a real-world reference cohort in recurrent, previously irradiated OCC, and favorable PFS were observed in patients with a higher CPS and peripheral B cell proportion. Further randomized trials are warranted.
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The computational complexity of transformers limits it to be widely deployed onto frameworks for visual recognition. Recent work Dosovitskiy et al. 2021 significantly accelerates the network processing speed by reducing the resolution at the beginning of the network, however, it is still hard to be directly generalized onto other downstream tasks e.g.object detection and segmentation like CNN. In this paper, we present a transformer-based architecture retaining both the local and global interactions within the network, and can be transferable to other downstream tasks. The proposed architecture reforms the original full spatial self-attention into pixel-wise local attention and patch-wise global attention. Such factorization saves the computational cost while retaining the information of different granularities, which helps generate multi-scale features required by different tasks. By exploiting the factorized attention, we construct a Separable Transformer (SeT) for visual modeling. Experimental results show that SeT outperforms the previous state-of-the-art transformer-based approaches and its CNN counterparts on three major tasks including image classification, object detection and instance segmentation.1.
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Precancerous lesions of the oral mucosa, especially those accompanied by moderate to severe dysplasia, contribute to the initiation of oral squamous cell carcinoma (OSCC). However, the cellular compositions and spatial organization of the precancerous stage and how these factors promote human OSCC initiation remain unclear. Here, we built a single-cell transcriptome atlas and a spatial transcriptome map after obtaining data from pairwise human oral mucosal biopsies of 9 individuals consisting of very early-stage OSCC, adjacent precancerous lesions with moderate to severe dysplasia, as well as a matched normal region. An altered epithelial gene-expression profile was identified which favored OSCC initiation. This observation was coupled with distinct fibroblast, monocytic, and regulatory T-cell subclusters involved in reshaping the microenvironment. In particular, a unique immune-inhibitory monocyte subtype and spatial-switching regulation of VEGF signaling were observed surrounding precancerous lesions, concertedly strengthening activities in promoting cancer initiation. Collectively, our work elucidated the cellular landscapes and roles of precancerous lesions underlying OSCC initiation, which is essential for understanding the entire OSCC initiation process and helps inform therapeutic strategies for cancer intervention.