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The use of Bruton tyrosine kinase inhibitors, such as ibrutinib, to block B-cell receptor signaling has achieved a remarkable clinical response in several B-cell malignancies, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and affects the long-term survival of these patients. Here, we demonstrate that the transcription factor early growth response gene 1 (EGR1) is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through the transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular adenosine triphosphate production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.
Assuntos
Antineoplásicos , Linfoma Difuso de Grandes Células B , Linfoma de Célula do Manto , Metformina , Humanos , Adulto , Animais , Camundongos , Tirosina Quinase da Agamaglobulinemia/metabolismo , Fosforilação Oxidativa , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Linfoma Difuso de Grandes Células B/patologia , Metformina/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/metabolismoRESUMO
Although thymus-independent donor-derived T cell expansion may determine the occurrence of graft-versus-host disease (GVHD) and relapse after transplantation, the characteristics and dynamics of the expansion process remain unclear. To address this issue, we monitored T cell receptor ß repertoire at day 0, day 28, and day 61 after transplantation in 30 patients with hematologic malignancies by next-generation sequencing. The clonality index showed an increasing clonality over time (P = .001). The top 200 clonotypes accounted for more than half of the total clonotypes (median frequency, 63.55%) at day 61, and there was a remarkable overlapping between the top 200 clonotypes of each repertoire and its former repertoire (>50%). A normalized index, called the T Cell Response Index (TCRI), was designed on the basis of rank-shift analysis to quantify antigen-driven expansion. The TCRI during the first month was not related to relapse or GVHD (P> .05), whereas the TCRI during the second month was related to relapse (P = .006). Recipients with a TCRI below 1.0 during the second month had a higher cumulative relapse rate (31.25% versus 0%, P = .0323) and had a lower 1-year survival rate (56.25% versus 78.57%, P = .281). The clonotypes with strong competitiveness in the second month in the nonrelapse group preferentially used TRBV2, TRBV12-3, TRBJ1-1 and TRBJ1-5 segments (P< .01). In conclusion, homeostatic expansion predominates in the first month due to nonspecific T cell proliferation, whereas antigen-driven expansion predominates in the second month and results in a graft-versus-tumor (GvT) effect. Moreover, TCRI could serve as a quantitative indicator of GvT against relapse within the first year. The difference in V and J segment usage reveals that T cells responsible for potent GvT effect are similar among patients.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Proliferação de Células , Humanos , Recidiva Local de Neoplasia , Linfócitos TRESUMO
BACKGROUND: Sweet osmanthus (Osmanthus fragrans Lour.) is one of the top ten traditional ornamental flowers in China. The flowering time of once-flowering cultivars in O. fragrans is greatly affected by the relatively low temperature, but there are few reports on its molecular mechanism to date. A hypothesis had been raised that genes related with flower opening might be up-regulated in response to relatively low temperature in O. fragrans. Thus, our work was aimed to explore the underlying molecular mechanism of flower opening regulated by relatively low temperature in O. fragrans. RESULTS: The cell size of adaxial and abaxial petal epidermal cells and ultrastructural morphology of petal cells at different developmental stages were observed. The cell size of adaxial and abaxial petal epidermal cells increased gradually with the process of flower opening. Then the transcriptomic sequencing was employed to analyze the differentially expressed genes (DEGs) under different number of days' treatments with relatively low temperatures (19 °C) or 23 °C. Analysis of DEGs in Gene Ontology analysis showed that "metabolic process", "cellular process", "binding", "catalytic activity", "cell", "cell part", "membrane", "membrane part", "single-organism process", and "organelle" were highly enriched. In KEGG analysis, "metabolic pathways", "biosynthesis of secondary metabolites", "plant-pathogen interaction", "starch and sucrose metabolism", and "plant hormone signal transduction" were the top five pathways containing the greatest number of DEGs. The DEGs involved in cell wall metabolism, phytohormone signal transduction pathways, and eight kinds of transcription factors were analyzed in depth. CONCLUSIONS: Several unigenes involved in cell wall metabolism, phytohormone signal transduction pathway, and transcription factors with highly variable expression levels between different temperature treatments may be involved in petal cell expansion during flower opening process in response to the relatively low temperature. These results could improve our understanding of the molecular mechanism of relatively-low-temperature-regulated flower opening of O. fragrans, provide practical information for the prediction and regulation of flowering time in O. fragrans, and ultimately pave the way for genetic modification in O. fragrans.
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Flores/genética , Oleaceae/genética , Reguladores de Crescimento de Plantas/metabolismo , Proteínas de Plantas/genética , Transdução de Sinais/genética , Transcriptoma , Temperatura Baixa , Flores/crescimento & desenvolvimento , Flores/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Oleaceae/crescimento & desenvolvimento , Oleaceae/fisiologia , Fatores de Transcrição/genéticaRESUMO
AIM AND OBJECTIVE: To explore nurses' experiences regarding shift patterns while providing front-line care for COVID-19 patients in isolation wards of hospitals in Shanghai and Wuhan during the novel coronavirus pandemic. Our findings will help to optimise shift work scheduling, use the existing nursing workforce more efficiently and improve nursing quality. BACKGROUND: Nurses are one of the main professionals fighting against COVID-19. Providing care for COVID-19 patients is challenging. In isolation wards, the workload has increased, and the workflow and shift patterns are completely different from the usual. More importantly, there is a shortage of nurses. Therefore, it is essential and urgent to arrange nurses' shifts correctly and use the existing workforce resources efficiently. DESIGN: A qualitative descriptive study of 14 nurses in Chinese hospitals was conducted. METHODS: Semi-structured interviews were used based on the phenomenological research method; data were analysed using Colaizzi's method of data analysis. This study aligns with the COREQ checklist. RESULTS: Four themes were extracted: assess the competency of nurses to assign nursing work scientifically and reasonably, reorganise nursing workflow to optimise shift patterns, communicate between managers and front-line nurses to humanise shift patterns, and nurses' various feelings and views on shift patterns. CONCLUSION: It is necessary to arrange shift patterns scientifically and allocate workforce rationally to optimise nursing workforce allocation, reduce nurses' workload, improve nursing quality and promote physical and mental health among nurses during the COVID-19 pandemic. RELEVANCE TO CLINICAL PRACTICE: This study emphasised nurses' experiences on shift patterns in isolation wards, providing useful information to manage shift patterns. Nursing managers should arrange shifts scientifically, allocate nursing workforce rationally, formulate emergency plans and establish emergency response rosters during the COVID-19 pandemic.
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COVID-19/enfermagem , Recursos Humanos de Enfermagem Hospitalar/organização & administração , Admissão e Escalonamento de Pessoal/organização & administração , Fluxo de Trabalho , Adulto , China , Feminino , Humanos , Pessoa de Meia-Idade , Pandemias , Pesquisa Qualitativa , SARS-CoV-2 , Carga de Trabalho/psicologiaRESUMO
Medulloblastoma (MB) stands as one of the prevalent malignant brain tumors among pediatric patients. Despite its prevalence, the intricate interplay between the regulatory program driving malignancy in MB cells and their interactions with the microenvironment remains insufficiently understood. Leveraging the capabilities of single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq), the chromatin accessibility landscape is unveiled across 59,015 distinct MB cells. This expansive dataset encompasses cells belonging to discrete molecular subgroups, namely SHH, WNT, Group3, and Group4. Within these chromatin accessibility profiles, specific regulatory elements tied to individual subgroups are uncovered, shedding light on the distinct activities of transcription factors (TFs) that likely orchestrate the tumorigenesis process. Moreover, it is found that certain neurotransmitter receptors (NTRs) are subgroup-specific and can predict MB subgroup classification when combined with their associated transcription factors. Notably, targeting essential NTRs within tumors influences both the in vitro sphere-forming capability and the in vivo tumorigenic capacity of MB cells. These findings collectively provide fresh insights into comprehending the regulatory networks and cellular dynamics within MBs. Furthermore, the significance of the TF-NTR regulatory circuits is underscored as prospective biomarkers and viable therapeutic targets.
Assuntos
Neoplasias Cerebelares , Cromatina , Meduloblastoma , Análise de Célula Única , Fatores de Transcrição , Meduloblastoma/genética , Meduloblastoma/metabolismo , Humanos , Análise de Célula Única/métodos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Cromatina/metabolismo , Cromatina/genética , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Camundongos , Animais , Linhagem Celular TumoralRESUMO
PURPOSE: To construct a virtual simulation teaching platform for in-hospital emergency nursing of craniofacial injury patients by virtual simulation technology, and to evaluate its application effect. METHODS: Through virtual reality, animation, human-computer interaction and other technologies, a 3D experiment scene based on high simulation virtual human was constructed to reproduce the virtual rescue scenes of craniofacial injury patients, such as emergency reception, first-aid cooperation, massive hemorrhage rescue cooperation, and tracheotomy cooperation in emergency rescue of sudden airway obstruction, and exercise modules and assessment modules were set. In the virtual simulation platform, the students used the holistic nursing theory and the PDCA cycle method to observe, evaluate and care for craniofacial injury patients. Preliminary evaluation of the platform was carried out in the training of 62 dental nurses. RESULTS: The virtual simulation platform could improve students' comprehensive first-aid ability for craniofacial injury patients. The item with the highest satisfaction rate for the virtual simulation platform was the consistency between the content of the virtual simulation platform and the theoretical course (the satisfaction rate was 91.9%), and the lowest satisfaction rate was the convenience of the virtual simulation platform operation and the page setting (the satisfaction rate was 80.6%). The evaluation module of the virtual simulation platform showed that the highest score of the comprehensive evaluation was 97, the lowest score was 56, and the average score was 80.2. CONCLUSIONS: The virtual simulation teaching platform for in-hospital first aid of craniofacial injury patients can create an immersive learning mode, provide an intuitive rescue experience to the students, and improve their comprehensive first-aid ability.
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Enfermagem em Emergência , Humanos , Aprendizagem , Competência ClínicaRESUMO
The infinite-layer nickelates, isostructural to the high-Tc cuprate superconductors, have emerged as a promising platform to host unconventional superconductivity and stimulated growing interest in the condensed matter community. Despite considerable attention, the superconducting pairing symmetry of the nickelate superconductors, the fundamental characteristic of a superconducting state, is still under debate. Moreover, the strong electronic correlation in the nickelates may give rise to a rich phase diagram, where the underlying interplay between the superconductivity and other emerging quantum states with broken symmetry is awaiting exploration. Here, we study the angular dependence of the transport properties of the infinite-layer nickelate Nd0.8Sr0.2NiO2 superconducting films with Corbino-disk configuration. The azimuthal angular dependence of the magnetoresistance (R(φ)) manifests the rotational symmetry breaking from isotropy to four-fold (C4) anisotropy with increasing magnetic field, revealing a symmetry-breaking phase transition. Approaching the low-temperature and large-magnetic-field regime, an additional two-fold (C2) symmetric component in the R(φ) curves and an anomalous upturn of the temperature-dependent critical field are observed simultaneously, suggesting the emergence of an exotic electronic phase. Our work uncovers the evolution of the quantum states with different rotational symmetries in nickelate superconductors and provides deep insight into their global phase diagram.
RESUMO
Itinerant kagome lattice magnets exhibit many novel correlated and topological quantum electronic states with broken time-reversal symmetry. Superconductivity, however, has not been observed in this class of materials, presenting a roadblock in a promising path toward topological superconductivity. Here, we report that novel superconductivity can emerge at the interface of kagome Chern magnet TbMn6Sn6 and metal heterostructures when elemental metallic thin films are deposited on either the top (001) surface or the side surfaces. Superconductivity is also successfully induced and systematically studied by using various types of metallic tips on different TbMn6Sn6 surfaces in point-contact measurements. The anisotropy of the superconducting upper critical field suggests that the emergent superconductivity is quasi-two-dimensional. Remarkably, the interface superconductor couples to the magnetic order of the kagome metal and exhibits a hysteretic magnetoresistance in the superconducting states. Taking into account the spin-orbit coupling, the observed interface superconductivity can be a surprising and more realistic realization of the p-wave topological superconductors theoretically proposed for two-dimensional semiconductors proximity-coupled to s-wave superconductors and insulating ferromagnets. Our findings of robust superconductivity in topological-Chern-magnet/metal heterostructures offer a new direction for investigating spin-triplet pairing and topological superconductivity.
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AIM: To investigate the professional identities and the willingness of nurses to respond to the call for support during the COVID-19 epidemic. BACKGROUND: The COVID-19 epidemic has resulted in nearly 300 million cases worldwide, causing more than five million deaths. However, the professional identities and the willingness of nurses to provide support during the COVID-19 epidemic in China remain unclear. METHODS: A total of 1,505 eligible nurses from 120 hospitals during the COVID-19 outbreak in China were included. Questionnaires were used to evaluate the willingness of these nurses to participate in epidemic control efforts. The Nurses' Professional Identity Scale was used to measure their sense of professional identity. RESULTS: About 90% of the nurses were willing to lend support in Hubei Province during the epidemic. The most common reason (93.84%) was found to be their beliefs as medical personnel in helping others in need. Nearly 10% of the nurses were unwilling to go to Hubei, primarily due to family reasons. The average total score of the Professional Identity Scale for all nurses reached a moderate to high level as indication of professional identity (116-125). Nurses who were willing to go to Hubei had a significantly higher total score than those who were not. CONCLUSIONS: The professional identity of nurses in China improved during the epidemic, and those with higher professional identities were more likely to respond to calls for support during the epidemic.
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COVID-19 , Enfermeiras e Enfermeiros , China/epidemiologia , Surtos de Doenças , Humanos , Inquéritos e QuestionáriosRESUMO
Flexoelectricity is a type of ubiquitous and prominent electromechanical coupling, pertaining to the electrical polarization response to mechanical strain gradients that is not restricted by the symmetry of materials. However, large elastic deformation is usually difficult to achieve in most solids, and the strain gradient at minuscule is challenging to control. Here, we exploit the exotic structural inhomogeneity of grain boundary to achieve a huge strain gradient (~1.2 nm-1) within 3-4-unit cells, and thus obtain atomic-scale flexoelectric polarization of up to ~38 µC cm-2 at a 24° LaAlO3 grain boundary. Accompanied by the generation of the nanoscale flexoelectricity, the electronic structures of grain boundaries also become different. Hence, the flexoelectric effect at grain boundaries is essential to understand the electrical activities of oxide ceramics. We further demonstrate that for different materials, altering the misorientation angles of grain boundaries enables tunable strain gradients at the atomic scale. The engineering of grain boundaries thus provides a general and feasible pathway to achieve tunable flexoelectricity.
RESUMO
A preliminary screening assay based on a microbial chromogenic reaction was developed to detect common antibiotic residues in meat rapidly. The assay comprised two bioassays: one for Escherichia coli and another for Geobacillus stearothermophilus. The assay was optimized and evaluated for the simultaneous screening of 30 antibiotics from five common antibiotic classes (tetracyclines, aminoglycosides, macrolides, ß-lactams, and quinolones) found in meat. Extraction using phosphate-acetonitrile buffer (pH 7.2) and a delipidating treatment using n-hexane resulted in a high extraction efficacy for the five antibiotics, without affecting the microbial color reaction. A carrier, polyvinyl alcohol (0.1 g/mL); a cross-linking agent, boric acid-sodium tetraborate solution (pH 5.5); and a bacterial suspension with an initial optical density of 1.0 were the optimal embedding conditions for stability, microbial activity, and chromogenic efficiency. The assay exhibited a 6-month shelf life, with detection limits of 40-60, 60-140, 60-100, 20-40, and 40-180 µg/kg for tetracyclines, aminoglycosides, macrolides, ß-lactams, and quinolones, respectively, which met the European Commission (37/2010) requirements for antibiotic residue limits. Our assay results were confirmed using LC-MS/MS with 160 samples, revealing a good correlation. This study demonstrates a reliable, easy-to-use, and economical method for preliminary screening of antibiotic residues in meat. This method may find an immediate application in food safety and general testing laboratories.