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The inherent benefits of aqueous Zn-ion batteries (ZIBs), such as environmental friendliness, affordability, and high theoretical capacity, render them promising candidates for energy storage systems. Nevertheless, the Zn anodes of ZIBs encounter severe challenges, including dendrite formation, hydrogen evolution reaction, corrosion, and surface passivation. These would result in the infeasibility of ZIBs in practical situations. To this end, artificial interfaces with functionalized materials are crafted to protect the Zn anode. They have the capability to modulate the zinc ion flux in proximity to the electrode surface and shield it from aqueous electrolytes by leveraging either size effects or charge effects. Considering metal-organic frameworks (MOFs) with tunable pore size, chemical composition, and stable framework structures, they have emerged as effective materials for building artificial interfaces, prolonging the lifespan, and improving the unitization of Zn anode. In this review, the contributions of MOFs for protecting Zn anode, which mainly involves facilitating homogeneous nucleation, manipulating selective deposition, regulating ion and charge flux, accelerating Zn desolvation, and shielding against free water and anions are comprehensively summarized. Importantly, the future research trajectories of MOFs for the protection of the Zn anode are underscored, which may propose new perspectives on the practical Zn anode and endow the MOFs with high-value applications.
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mRNA-based therapeutics are revolutionizing the landscape of medical interventions. However, the short half-life of mRNA and transient protein expression often limits its therapeutic potential, demanding high treatment doses or repeated administrations. Self-replicating RNA (RepRNA)-based treatments could offer enhanced protein production and reduce the required dosage. Here, we developed polymeric micelles based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) block copolymers modified with phenylalanine (Phe) moieties via biodegradable ester bonds for the efficient delivery of RepRNA. These polymers successfully encapsulated RepRNA into sub-100 nm micelles assisted by the hydrophobicity of the Phe moieties and their ability to π-π stack with the bases in RepRNA. The micelles made from Phe-modified PEG-PG (PEG-PG(Phe)) effectively maintained the integrity of the loaded RepRNA in RNase-rich serum conditions. Once taken up by cells, the micelles triggered a pH-responsive membrane disruption, promoted by the strong protonation of the amino groups at endosomal pH, thereby delivering the RepRNA to the cytosol. The system induced strong protein expression in vitro and outperformed commercial transfecting reagents in vivo, where it resulted in enhanced and long-lasting protein expression.
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Micelas , Fenilalanina , ARN , Línea Celular Tumoral , Concentración de Iones de Hidrógeno , Polímeros/química , Polietilenglicoles/química , ARN Mensajero , Portadores de Fármacos/químicaRESUMEN
Optimizing catalysts for competitive photocatalytic reactions demand individually tailored band structure as well as intertwined interactions of light absorption, reaction activity, mass, and charge transport. Here, a nanoparticulate host-guest structure is rationally designed that can exclusively fulfil and ideally control the aforestated uncompromising requisites for catalytic reactions. The all-inclusive model catalyst consists of porous Co3 O4 host and Znx Cd1- x S guest with controllable physicochemical properties enabled by self-assembled hybrid structure and continuously amenable band gap. The effective porous topology nanoassembly, both at the exterior and the interior pores of a porous metal-organic framework (MOF), maximizes spatially immobilized semiconductor nanoparticles toward high utilization of particulate heterojunctions for vital charge and reactant transfer. In conjunction, the zinc constituent band engineering is found to regulate the light/molecules absorption, band structure, and specific reaction intermediates energy to attain high photocatalytic CO2 reduction selectivity. The optimal catalyst exhibits a H2 -generation rate up to 6720 µmol g-1 h-1 and a CO production rate of 19.3 µmol g-1 h-1 . These findings provide insight into the design of discrete host-guest MOF-semiconductor hybrid system with readily modulated band structures and well-constructed heterojunctions for selective solar-to-chemical conversion.
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BACKGROUND: Even though chemotherapy-induced nausea and vomiting (CINV) can be well controlled in the acute phase, the incidence of delayed CINV remains high. In this study, we intend to investigate whether prolonged use of NK-1 receptor antagonist (RA) in addition to 5-HT3 RA and dexamethasone (DEX) was more effective in preventing delayed CINV. METHODS: This randomised, open-label, controlled study was designed to compare the efficacy and safety of fosaprepitant 150 mg given on days 1,3 (prolonged group) versus on day 1 (regular group) in patients receiving highly emetogenic chemotherapy (HEC). All patients also treated with palonosetron on day 1 and DEX on days 1-3. The primary endpoint was the incidence of delayed nausea and vomiting. The second endpoint was AEs. All the above endpoints were defined according to CTCAE 5.0. RESULTS: Seventy-seven patients were randomly assigned to prolonged group and seventy-nine to regular group. Prolonged group demonstrated superiority in controlling delayed CINV to regular group, with statistically significant lower incidence of nausea (6.17% vs 12.66%, P = 0.0056), and slightly lower incidence of grade 1 vomiting (1.62% vs 3.80%, P = 0.0953) in the delayed phase. In addition, prolonged use of fosaprepitant was safe. No significant difference was found between the two groups regarding constipation, diarrhea, hiccough, fatigue, palpitation and headache in delayed phase. CONCLUSIONS: Prolonged use of fosaprepitant can effectively and safely prevent delayed CINV in patients receiving HEC.
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Antineoplásicos , Náusea , Humanos , Náusea/inducido químicamente , Náusea/prevención & control , Vómitos/inducido químicamente , Vómitos/prevención & control , Morfolinas/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , China/epidemiología , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Progresión de la Enfermedad , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Femenino , Estudios de Seguimiento , Amplificación de Genes , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Factor 88 de Diferenciación Mieloide/genética , Prednisona/farmacología , Prednisona/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Estudios Retrospectivos , Rituximab/farmacología , Rituximab/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Vincristina/farmacología , Vincristina/uso terapéutico , Adulto JovenRESUMEN
Electroreduction of CO2 into formic acid (HCOOH) is of particular interest as a hydrogen carrier and chemical feedstock. However, its conversion is limited by a high overpotential and low stability due to undesirable catalysts and electrode design. Herein, an integrated 3D bismuth oxide ultrathin nanosheets/carbon foam electrode is designed by a sponge effect and N-atom anchor for energy-efficient and selective electrocatalytic conversion of CO2 to HCOOH for the first time. Benefitting from the unique 3D array foam architecture for highly efficient mass transfer, and optimized exposed active sites, as confirmed by density functional theory calculations, the integrated electrode achieves high electrocatalytic performance, including superior partial current density and faradaic efficiency (up to 94.1 %) at a moderate overpotential as well as a high energy conversion efficiency of 60.3 % and long-term durability.
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BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Previous studies revealed that miR-183-5p is frequently involved in various human cancers. However, the exact role of miR-183-5p in regulating the pathogenesis of lung cancer remains unclear. METHOD: Bioinformatic analysis, luciferase reporter assay, and Western blotting was used to investigate whether miR-183-5p directly bound to the 3'UTR of PIK3CA and prevented its translation. Furthermore, an si-miR-183-5p and PIK3CA siRNA was used to evaluate whether PIK3CA expression increased and whether cell proliferation, migration and invasion ability were promoted. RESULTS: miR-183-5p directly bound to the 3'UTR of PIK3CA and prevented its translation. miR-183-5p also acted as a tumor suppressor, and contrary to most studies, its expression was downregulated in lung cancer. Functional studies revealed that overexpression of miR-183-5p reduced cell proliferation, migration, and invasion and that miR-183-5p induced cell cycle arrest and increased cell apoptosis. PIK3CA expression, cell proliferation, migration and invasion ability increased. siRNA-mediated silencing of PIK3CA in lung cancer cells decreased their proliferation and invasive capabilities, suggesting that miR-183-5p inhibited cell proliferation and invasion of lung cancer cells at least partly through downstream targeting of PIK3CA. CONCLUSION: Our studies suggest that miR-183-5p may function as a tumor suppressor in lung cancer via the miR-183-5p/PIK3CA regulatory axis and identify a potentially effective therapeutic strategy for lung cancer.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Regiones no Traducidas 3'/genética , Células A549 , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica/genética , Genes Supresores de Tumor/fisiología , Humanos , ARN Interferente Pequeño/genéticaRESUMEN
In the US, lung carcinoma accounted for over 150,000 deaths in 2018 and the advances in increasing survival rates are still limited. In this study, we investigated the cohorts with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) from The Cancer Genome Atlas to figure out the risk factors and genomic alterations that affected their prognosis. The histoclinical factors that differed between LUAD and LUSC were identified and the risk factors affecting the overall survival were figured out for both LUAD and LUSC. Next, the patterns of nucleotides substitutions and the mutational signatures were extracted to illustrate whether different mutational processes performed for them. Finally, the genes that had different frequencies of mutation were identified. LUAD and LUSC presented differences in histoclinical factors including age at the time of diagnosis, sex, smoking history, pathological T classification, and overall survival. This was caused by the distinct genomic alterations including the transition-to-transversion ratios, mutational signatures, and the frequently mutated genes. We proposed that the mutational signature associated with aging could be used to predict the prognosis of patients with LUAD. On the other hand, the AID/APOBEC family was associated with the prognosis of LUSC. Finally, SNTG1 and LRRK2 might be important in LUAD and LUSC, respectively.
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Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutación , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Tasa de Mutación , Pronóstico , Factores de Riesgo , Factores de Tiempo , TranscriptomaRESUMEN
The electrochemical N2 fixation, which is far from practical application in aqueous solution under ambient conditions, is extremely challenging and requires a rational design of electrocatalytic centers. We observed that bismuth (Bi) might be a promising candidate for this task because of its weak binding with H adatoms, which increases the selectivity and production rate. Furthermore, we successfully synthesized defect-rich Bi nanoplates as an efficient noble-metal-free N2 reduction electrocatalyst via a low-temperature plasma bombardment approach. When exclusively using 1 Hâ NMR measurements with N2 gas as a quantitative testing method, the defect-rich Bi(110) nanoplates achieved a 15 NH3 production rate of 5.453â µg mgBi -1 h-1 and a Faradaic efficiency of 11.68 % at -0.6â V vs. RHE in aqueous solution at ambient conditions.
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Large-scale application of renewable energy and rapid development of electric vehicles have brought unprecedented demand for advanced energy-storage/conversion technologies and equipment. Rechargeable zinc (Zn)-air batteries represent one of the most promising candidates because of their high energy density, safety, environmental friendliness, and low cost. The air electrode plays a key role in managing the many complex physical and chemical processes occurring on it to achieve high performance of Zn-air batteries. Herein, recent advances of air electrodes from bifunctional catalysts to architectures are summarized, and their advantages and disadvantages are discussed to underline the importance of progress in the evolution of bifunctional air electrodes. Finally, some challenges and the direction of future research are provided for the optimized design of bifunctional air electrodes to achieve high performance of rechargeable Zn-air batteries.
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BACKGROUND AND AIM: 5-Fluorouracil (5-Fu) is one of the most commonly prescribed antineoplastic agents against gastric and colorectal cancers. Continuous infusion would be the optimal way of its administration, however, may usually cause thrombosis, infection, and prolonged hospital stay. Oral fluoropyrimidines would be an attractive alternative, but their efficiency and toxicities for the treatment of gastric and colorectal cancer are still obscure as compared with infusion 5-Fu. METHODS: Literature retrieval, trials selection and assessment, data collection, and statistic analysis were performed according to the Cochrane Handbook. The outcome measures were tumor response rate, progression-free survival, overall survival, and adverse effects. RESULTS: Twenty-nine randomized controlled trials, comprising totally 15 154 patients, were included. Meta-analysis showed similar overall outcome in terms of response rate (1.01; 95% confidence interval [CI], 0.92-1.12), progression-free survival (hazard ratio 1.00; 95%CI, 0.94-1.06), and overall survival (hazard ratio 0.96; 95%CI, 0.92-1.01) between oral fluoropyrimidine-based and intravenous 5-Fu-based regimens in gastric and colorectal cancer patients. The risk of grade 3/4 neutropenia, thrombocytopenia, and stomatitis was more prominent in intravenous 5-Fu-based regimens; while more frequent grade 3/4 hand-foot syndrome, diarrhea, and anorexia were detected in oral fluoropyrimidine-based regimens. CONCLUSIONS: Oral-fluoropyrimidines showed equivalent response and similar survival outcomes, but different toxicity profiles, as compared with intravenous 5-Fu. Thus, it would be a more convenient and adjustable alternative in treatment of advanced gastric and colorectal cancer.
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Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Pirimidinas/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Administración Oral , Antineoplásicos/efectos adversos , Neoplasias Colorrectales/mortalidad , Bases de Datos Bibliográficas , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/efectos adversos , Síndrome Mano-Pie/epidemiología , Síndrome Mano-Pie/etiología , Humanos , Infusiones Intravenosas , Masculino , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Pirimidinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Gástricas/mortalidad , Estomatitis/inducido químicamente , Estomatitis/epidemiología , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Resultado del TratamientoRESUMEN
PeaT1 is a proteinaceous elicitor from fungal pathogen Alternaria tenuissima. Our previous research revealed that this elicitor could induce defense response and enhance disease resistance in various plants including Nicotiana plants. However, immune activation mechanisms whereby PeaT1 elicits defense response remain unclear. In this study, the association between elicitor protein PeaT1 and the plasma membrane was assessed using the FITC (Fluorescein isothiocyanate) labeling method. A PeaT1-interacting protein was isolated via 125I-PeaT1 cross-linking and Far Western blot analyses, and designated PtBP1 (PeaT1 Binding Protein 1). From the data of Mass spectrometry (MS) and bioinformatics analysis, the 22 kDa plasma membrane protein PtBP1 was inferred to be a member of DREPP (developmentally regulated plasma membrane polypeptide) family that is induced in plants under stress conditions and might get involved in downstream signaling. For further verification of this association, Far Western blot, co-immunoprecipitation and bimolecular fluorescence complementation (BiFC) analyses were performed, showing PtBP1 could bind with PeaT1 in vitro and in vivo. Virus-induced gene silencing (VIGS) analysis exhibited that PtBP1 silencing in Nicotiana benthamiana attenuated tobacco mosaic virus (TMV) resistance compared to the tobacco rattle virus (TRV) control after PeaT1 treatment.
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Alternaria/genética , Resistencia a la Enfermedad , Proteínas Fúngicas/metabolismo , Nicotiana/inmunología , Enfermedades de las Plantas/inmunología , Proteínas de Plantas/metabolismo , Virus del Mosaico del Tabaco/inmunología , Alternaria/metabolismo , Proteínas Fúngicas/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Enfermedades de las Plantas/microbiología , Hojas de la Planta/genética , Hojas de la Planta/inmunología , Hojas de la Planta/fisiología , Hojas de la Planta/virología , Proteínas de Plantas/genética , Unión Proteica , Transducción de Señal , Nicotiana/genética , Nicotiana/fisiología , Nicotiana/virologíaRESUMEN
Flexible power sources with high energy density are crucial for the realization of next-generation flexible electronics. Theoretically, rechargeable flexible zinc-air (Zn-air) batteries could provide high specific energy, while their large-scale applications are still greatly hindered by high cost and resources scarcity of noble-metal-based oxygen evolution reaction (OER)/oxygen reduction reaction (ORR) electrocatalysts as well as inferior mechanical properties of the air cathode. Combining metallic Co4N with superior OER activity and Co-N-C with perfect ORR activity on a free-standing and flexible electrode could be a good step for flexible Zn-air batteries, while lots of difficulties need to be overcome. Herein, as a proof-of-concept experiment, we first propose a strategy for in situ coupling of strung Co4N and intertwined N-C fibers, by pyrolyzation of the novel pearl-like ZIF-67/polypyrrole nanofibers network rooted on carbon cloth. Originating from the synergistic effect of Co4N and Co-N-C and the stable 3D interconnected conductive network structure, the obtained free-standing and highly flexible bifunctional oxygen electrode exhibits excellent electrocatalytic activity and stability for both OER and ORR in terms of low overpotential (310 mV at 10 mA cm(-2)) for OER, a positive half-wave potential (0.8 V) for ORR, and a stable current density retention for at least 20 h, and especially, the obtained Zn-air batteries exhibit a low discharge-charge voltage gap (1.09 V at 50 mA cm(-2)) and long cycle life (up to 408 cycles). Furthermore, the perfect bendable and twistable and rechargeable properties of the flexible Zn-air battery particularly make it a potentially power portable and wearable electronic device.
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Developing effective ways to recycle rusted stainless steel and to promote the sluggish oxygen evolution reaction (OER), associated with water splitting and metal-air batteries, is important for a resource-sustainable and environment-friendly society. Herein, we propose a strategy to enable rusted stainless steel plate to be used as an abundant and low-cost OER catalyst, wherein a hydrothermal combined inâ situ electrochemical oxidation-reduction cycle (EORC) method is developed to mimic and expedite the corrosion process, and thus activate stainless steel into free-standing OER electrodes. Benefiting from the plentiful electrolyte-accessible Fe/(Ni) oxyhydroxides, high conductivity and mechanical stability, this electrode exhibits remarkable OER performances including low overpotential, fast kinetics, and long-term durability. The slight degradation in current after long-term use can be repaired immediately inâ situ by an EORC.
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Polydopamine (PDA), which is biodegradable and is derived from naturally occurring products, can be employed as an electrode material, wherein controllable partial oxidization plays a key role in balancing the proportion of redox-active carbonyl groups and the structural stability and conductivity. Unexpectedly, the optimized PDA derivative endows lithium-ion batteries (LIBs) or sodium-ion batteries (SIBs) with superior electrochemical performances, including high capacities (1818â mAh g(-1) for LIBs and 500â mAh g(-1) for SIBs) and good stable cyclabilities (93 % capacity retention after 580 cycles for LIBs; 100 % capacity retention after 1024 cycles for SIBs), which are much better than those of their counterparts with conventional binders.
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Suministros de Energía Eléctrica , Indoles/química , Litio/química , Polímeros/química , Sodio/química , Conductividad Eléctrica , Electrodos , Diseño de Equipo , Iones/química , Modelos Moleculares , Oxidación-ReducciónRESUMEN
Development of an efficient hydrogen evolution reaction (HER) catalyst composed of earth-abundant elements is scientifically and technologically important for the water splitting associated with the conversion and storage of renewable energy. Herein we report a new class of Co-C-N complex bonded carbon (only 0.22 at% Co) for HER with a self-supported and three-dimensional porous structure that shows an unexpected catalytic activity with low overpotential (212 mV at 100 mA cm(-2)) and long-term stability, better than that of most traditional-metal catalysts. Experimental observations in combination with density functional theory calculations reveal that C and N hybrid coordination optimizes the charge distribution and enhances the electron transfer, which synergistically promotes the proton adsorption and reduction kinetics.
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Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera (PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic activity. Using a novel iterative molecular docking-guided post-SELEX (systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully developed a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin-proteasome-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo, without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.
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Aptámeros de Nucleótidos , Neoplasias , Proteolisis , Proteína p53 Supresora de Tumor , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Humanos , Aptámeros de Nucleótidos/farmacología , Proteolisis/efectos de los fármacos , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Línea Celular Tumoral , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Técnica SELEX de Producción de Aptámeros , Cisplatino/farmacología , Cisplatino/uso terapéutico , Simulación del Acoplamiento Molecular , Mutación , Ensayos Antitumor por Modelo de Xenoinjerto , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratones DesnudosRESUMEN
Lung adenocarcinoma (LUAD) is prone to bone metastasis, resulting in poor prognosis. The present study aimed to detect the expression of deoxyribonuclease 1-like 3 (DNASE1L3) and forkhead-box P2 (FOXP2) in LUAD cells to investigate the role of DNASE1L3 in the regulation of proliferation, migration, invasion and tube formation of LUAD cells and how FOXP2 affects DNASE1L3 expression. The expression of DNASE1L3 and FOXP2 in LUAD cells was analyzed by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. The transfection efficiency of DNASE1L3 overexpression plasmids, FOXP2 overexpression or interference plasmids into A549 cells was also confirmed by RT-qPCR and western blotting. The viability, proliferation, migration and invasion and tube formation of LUAD cells following transfection was in turn detected by MTT, EdU staining, wound healing, Transwell and tube formation assay. The expression of proteins associated with epithelial-mesenchymal transformation and tube formation was detected by western blotting. Binding between DNASE1L3 and FOXP2 was confirmed by dual-luciferase reporter assay and chromatin immunoprecipitation. Gene Expression Profiling Interactive Analysis database predicted that underexpression of DNASE1L3 in LUAD was associated with poor prognosis. DNASE1L3 expression was decreased in LUAD cells and overexpression of DNASE1L3 inhibited the proliferation, migration, invasion and tube formation of LUAD cells. Transcription factor FOXP2 positively regulated DNASE1L3 transcription in LUAD cells. FOXP2 was also underexpressed in LUAD cells and downregulation of FOXP2 promoted proliferation, migration, invasion and tube formation of LUAD cells, which was reversed by overexpression of DNASE1L3. In conclusion, DNASE1L3 was positively regulated by transcription factor FOXP2 and overexpression inhibited proliferation, migration, invasion and tube formation of LUAD cells.
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With the development of sequencing technology, the detection rate of non-small cell lung cancer (NSCLC) with primary epidermal growth factor receptor (EGFR) T790M mutation is increasing. However, the first-line treatment for primary EGFR T790M-mutated NSCLC still lacks standard recommendations. Here, we reported three advanced NSCLC cases with EGFR-activating mutation and primary T790M mutation. The patients were initially treated with Aumolertinib combination with Bevacizumab; among which, one case was discontinued Bevacizumab due to bleeding risk after treatment for three months. Treatment was switched to Osimertinib after ten months of treatment. Another case switched to Osimertinib and discontinued Bevacizumab after thirteen months of treatment. The best effect response in all three cases was partial response (PR) after initial treatment. Two cases progressed after first-line treatment and progression-free survival (PFS) was eleven months and seven months respectively. The other one patient had persistent response after treatment, and the treatment duration has reached nineteen months. Two cases had multiple brain metastases before administration and the best response to intracranial lesions was PR. The intracranial PFS was fourteen months and not reached (16+ months), respectively. There were no new adverse events (AEs), and no AEs of grade three or above were reported. In addition, we summarized the research progress of Osimertinib in the treatment of NSCLC with primary EGFR T790M mutation. In conclusion, Aumolertinib combined with Bevacizumab in the treatment of advanced NSCLC with primary EGFR T790M mutation has a high objective response rate (ORR) and control ability of intracranial lesions, which can be used as one of the initial options for first-line advanced NSCLC with primary EGFR T790M mutation.â©.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Bevacizumab , Receptores ErbB , Mutación , Inhibidores de Proteínas QuinasasRESUMEN
Background: There are about 10-15% of uncommon EGFR mutations found in NSCLC patients, and their sensitivity to EGFR TKIs still lack sufficient clinical evidence, especially for rare compound mutations. Almonertinib is the third generation of EGFR-TKI that has demonstrated excellent efficacy in classical mutations, however, effects in rare mutations have also been rarely reported. Case presentation: In this case report, we present a patient with advanced lung adenocarcinoma with a rare EGFR p.V774M/p.L833V compound mutations, who achieved long-lasting and stable disease control after first-line Almonertinib targeted therapy. This case report could provide more information for therapeutic strategy selecting of NSCLC patients harboring rare EGFR mutations. Conclusion: We report for the first time the long-lasting and stable disease control with Almonertinib for EGFR p.V774M/p.L833V compound mutations treatment, hoping to provide more clinical case references for the treatment of rare compound mutations.