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Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large ß barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a ß propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the ß propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.
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Toxinas Bacterianas/química , Proteínas de Membrana/química , Proteínas do Tecido Nervoso/química , Sinapses/metabolismo , Processamento Alternativo , Motivos de Aminoácidos , Animais , Axônios , Adesão Celular , Linhagem Celular , AMP Cíclico/metabolismo , Feminino , Células HEK293 , Hormônios/química , Humanos , Insetos , Proteínas de Membrana/metabolismo , Camundongos , Conformação Molecular , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neuropeptídeos/química , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/química , Transdução de SinaisRESUMO
RNA transcribed from enhancers, i.e., eRNA, has been suggested to directly activate transcription by recruiting transcription factors and co-activators. Although there have been specific examples of eRNA functioning in this way, it is not clear how general this may be. We find that the AT-hook of SWI/SNF preferentially binds RNA and, as part of the esBAF complex, associates with eRNA transcribed from intronic and intergenic regions. Our data suggest that SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers, representative of two distinct stages that mimic early mammalian development, and not at enhancers that are shared between the two stages. In this manner, SWI/SNF facilitates recruitment and/or activation of MLL3/4, p300/CBP, and Mediator to stage-specific enhancers and super-enhancers that regulate the transcription of metabolic and cell lineage priming-related genes. These findings highlight a connection between ATP-dependent chromatin remodeling and eRNA in cell identity and typical- and super-enhancer activation.
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Linhagem da Célula , DNA Helicases , Elementos Facilitadores Genéticos , Proteínas Nucleares , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , DNA Helicases/metabolismo , DNA Helicases/genética , Linhagem da Célula/genética , Animais , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Humanos , Camundongos , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genéticaRESUMO
Perovskite bandgap tuning without quality loss makes perovskites unique among solar absorbers, offering promising avenues for tandem solar cells1,2. However, minimizing the voltage loss when their bandgap is increased to above 1.90 eV for triple-junction tandem use is challenging3-5. Here we present a previously unknown pseudohalide, cyanate (OCN-), with a comparable effective ionic radius (1.97 Å) to bromide (1.95 Å) as a bromide substitute. Electron microscopy and X-ray scattering confirm OCN incorporation into the perovskite lattice. This contributes to notable lattice distortion, ranging from 90.5° to 96.6°, a uniform iodide-bromide distribution and consistent microstrain. Owing to these effects, OCN-based perovskite exhibits enhanced defect formation energy and substantially decreased non-radiative recombination. We achieved an inverted perovskite (1.93 eV) single-junction device with an open-circuit voltage (VOC) of 1.422 V, a VOC × FF (fill factor) product exceeding 80% of the Shockley-Queisser limit and stable performance under maximum power point tracking, culminating in a 27.62% efficiency (27.10% certified efficiency) perovskite-perovskite-silicon triple-junction solar cell with 1 cm2 aperture area.
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T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRß). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.
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Terapia Baseada em Transplante de Células e Tecidos , Edição de Genes , Neoplasias , Medicina de Precisão , Receptores de Antígenos de Linfócitos T , Linfócitos T , Transgenes , Humanos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Biópsia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Síndrome da Liberação de Citocina/complicações , Progressão da Doença , Encefalite/complicações , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Mutação , Neoplasias/complicações , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Segurança do Paciente , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transgenes/genética , Antígenos HLA/imunologia , Sistemas CRISPR-CasRESUMO
Polycomb repressive complex 2 (PRC2), which mediates the deposition of H3K27me3 histone marks, is important for developmental decisions in animals and plants. In the shoot apical meristem (SAM), Three Amino acid Loop Extension family KNOTTED-LIKE HOMEOBOX /BEL-like (KNOX/BELL) transcription factors are key regulators of meristem cell pluripotency and differentiation. Here, we identified a PRC2-associated coiled-coil protein (PACP) that interacts with KNOX/BELL transcription factors in rice (Oryza sativa) shoot apex cells. A loss-of-function mutation of PACP resulted in differential gene expression similar to that observed in PRC2 gene knockdown plants, reduced H3K27me3 levels, and reduced genome-wide binding of the PRC2 core component EMF2b. The genomic binding of PACP displayed a similar distribution pattern to EMF2b, and genomic regions with high PACP- and EMF2b-binding signals were marked by high levels of H3K27me3. We show that PACP is required for the repression of cell differentiation-promoting genes targeted by a rice KNOX1 protein in the SAM. PACP is involved in the recruitment or stabilization of PRC2 to genes targeted by KNOX/BELL transcription factors to maintain H3K27me3 and gene repression in dividing cells of the shoot apex. Our results provide insight into PRC2-mediated maintenance of H3K27me3 and the mechanism by which KNOX/BELL proteins regulate SAM development.
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Oryza , Complexo Repressor Polycomb 2 , Animais , Diferenciação Celular/genética , Genes Homeobox , Histonas/genética , Histonas/metabolismo , Meristema/metabolismo , Oryza/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismoRESUMO
Circadian rhythms in metabolically active tissues are crucial for maintaining physical health. Circadian disturbance (CD) can cause various health issues, such as metabolic abnormalities and immune and cognitive dysfunctions. However, studies on the role of CD in immune cell development and differentiation, as well as the rhythmic expression of the core clock genes and their altered expression under CD, remain unclear. Therefore, we exposed C57bl/6j mice to repeated reversed light-dark cycles for 90 days to research the effects of CD on bone marrow (BM) hematopoietic function. We also researched the effects of CD on endogenous circadian rhythms, temporally dependent expression in peripheral blood and myeloid leukocytes, environmental homeostasis within BM, and circadian oscillations of hematopoietic-extrinsic cues. Our results confirmed that when the light and dark cycles around mice were frequently reversed, the circadian rhythmic expression of the two main circadian rhythm markers, the hypothalamic clock gene, and serum melatonin, was disturbed, indicating that the body was in a state of endogenous CD. Furthermore, CD altered the temporally dependent expression of peripheral blood and BM leukocytes and destroyed environmental homeostasis within the BM as well as circadian oscillations of hematopoietic-extrinsic cues, which may negatively affect BM hematopoiesis in mice. Collectively, these results demonstrate that circadian rhythms are vital for maintaining health and suggest that the association between CD and hematopoietic dysfunction warrants further investigation.
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Medula Óssea , Relógios Circadianos , Camundongos , Animais , Medula Óssea/metabolismo , Fotoperíodo , Ritmo Circadiano/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Camundongos Endogâmicos C57BL , Relógios Circadianos/genéticaRESUMO
Following meiotic recombination, each pair of homologous chromosomes acquires at least one crossover, which ensures accurate chromosome segregation and allows reciprocal exchange of genetic information. Recombination failure often leads to meiotic arrest, impairing fertility, but the molecular basis of recombination remains elusive. Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in patients with severe oligozoospermia owing to meiotic metaphase I arrest. The mutation abolishes M1AP foci on the chromosome axes, resulting in decreased recombination intermediates and crossovers in male mouse models. M1AP interacts with the mammalian ZZS (an acronym for yeast proteins Zip2-Zip4-Spo16) complex components, SHOC1, TEX11, and SPO16. M1AP localizes to chromosomal axes in a SPO16-dependent manner and colocalizes with TEX11. Ablation of M1AP does not alter SHOC1 localization but reduces the recruitment of TEX11 to recombination intermediates. M1AP shows cytoplasmic localization in fetal oocytes and is dispensable for fertility and crossover formation in female mice. Our study provides the first evidence that M1AP acts as a copartner of the ZZS complex to promote crossover formation and meiotic progression in males.
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Meiose , Complexos Multiproteicos , Animais , Feminino , Masculino , Camundongos , Meiose/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complexos Multiproteicos/metabolismoRESUMO
Cardiovascular disorders are commonly prevalent in cancer patients, yet the mechanistic link between them remains poorly understood. Because neutrophil extracellular traps (NETs) have implications not just in cardiovascular diseases (CVD), but also in breast cancer (BC), it was hypothesized to contribute to CVD in the context of oncogenesis. We established a mouse model using nude mice to simulate liver metastasis of triple-negative BC (TNBC) through the injection of MDA-MB-231 cells. Multiple imaging and analysis techniques were employed to assess the cardiac function and structure, including echocardiography, HE staining, Masson staining, and transmission electron microscopy (TEM). MDA-MB-231 cells underwent treatment with a CaSR inhibitor, CaSR agonist, and NF-κB channel blocker. The phosphorylation of NF-κB channel protein p65 and the expression and secretion of IL-8 were assessed using qRT-PCR, Western Blot, and ELISA, respectively. In addition, MDA-MB-231 cells were co-cultured with polymorphonuclear neutrophils (PMN) under varying conditions. The co-localization of PMN extracellular myeloperoxidase (MPO) and DNA were observed by cellular immunofluorescence staining to identify the formation of NETs. Then, the cardiomyocytes were co-cultured with the above medium that contains NETs or not, respectively; the effects of NETs on cardiomyocytes apoptosis were perceived by flow cytometry. The ultrastructural changes of myocardial cells were perceived by TEM, and ELISA detected the levels of myocardial enzyme (LDH, MDA and SOD). Overall, according to our research, CaSR has been found to have a regulatory role in IL-8 secretion in MDA-MB-231 cells, as well as in the formation of NETs by PMN cells. These findings suggest CaSR-mediated stimulation in PMN can lead to increased NETs formation and subsequently to cytotoxicity in cardiomyocytes, which potentially via activation of the NF-κB signaling cascade of BC cell.
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Doenças Cardiovasculares , Armadilhas Extracelulares , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , NF-kappa B , Receptores de Detecção de Cálcio , Miócitos Cardíacos , Interleucina-8 , Camundongos NusRESUMO
Dimensionality of materials is closely related to their physical properties. For two-dimensional (2D) semiconductors such as monolayer molybdenum disulfide (MoS2), converting them from 2D nanosheets to one-dimensional (1D) nanoscrolls could contribute to remarkable electronic and optoelectronic properties, yet the rolling-up process still lacks sufficient controllability, which limits the development of their device applications. Herein we report a modified solvent evaporation-induced rolling process that halts at intermediate states and achieve MoS2 nanoscrolls with high yield and decent axial uniformity. The accordingly fabricated nanoscroll memories exhibit an on/off ratio of â¼104 and a retention time exceeding 103 s and can realize multilevel storage with pulsed gate voltages. Such open-end, high-curvature, and hollow 1D nanostructures provide new possibilities to manipulate the hysteresis windows and, consequently, the charge storage characteristics of nanoscale field-effect transistors, thereby holding great promise for the development of miniaturized memories.
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The exceptional semiconducting properties of two-dimensional (2D) transition metal dichalcogenides (TMDs) have made them highly promising for the development of future electronic and optoelectronic devices. Extensive studies of TMDs are partly associated with their ability to generate 2D-confined hot carriers above the conduction band edges, enabling potential applications that rely on such transient excited states. In this work, room-temperature spatiotemporal hot carrier dynamics in monolayer MoS2 is studied by transient absorption microscopy (TAM), featuring an initial ultrafast expansion followed by a rapid negative diffusion, and ultimately a slow long-term expansion of the band edge C-excitons. We provide direct experimental evidence to identify the abnormal negative diffusion process as a spatial contraction of the hot carriers resulting from spatial variation in the hot phonon bottleneck effect due to the Gaussian intensity distribution of the pump laser beam.
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Efficient pure-red emission light-emitting diodes (LEDs) are essential for high-definition displays, yet achieving pure-red emission is hindered by challenges like phase segregation and spectral instability when using halide mixing. Additionally, strongly confined quantum dots (QDs) produced through traditional hot-injection methods face byproduct contamination due to poor solubility of metal halide salts in the solvent octadecene (ODE) at low temperatures. Herein, we introduced a novel method using a benzene-series strongly electrostatic potential solvent instead of ODE to prevent PbI2 intermediates and promote their dissolution into [PbI3]-. Increasing methyl groups on benzene yields precisely sized (4.4 ± 0.1 nm) CsPbI3 QDs with exceptional properties: a narrow 630 nm PL peak with photoluminescence quantum yield (PLQY) of 97%. Sequential ligand post-treatment optimizes optical and electrical performance of QDs. PeLEDs based on optimized QDs achieve pure-red EL (CIE: 0.700, 0.290) approaching Rec. 2020 standards, with an EQE of 25.2% and T50 of 120 min at initial luminance of 107 cd/m2.
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Colloidal quantum well (CQW) based light emitting diodes (LEDs) possess extra-high theoretical efficiency, but their performance still lags far behind conventional LEDs due to severe exciton quenching and unbalanced charge injection. Herein, we devised a gradient composition CdxZn1-xS shell to address these issues. The epitaxial shell with gradient composition was achieved through controlling competition between Cd2+ and Zn2+ cations to preferentially bind to the anions S2-. Thus, exciton quenching was suppressed greatly by passivating defects and reducing nonradiative recombination, thereby achieving near-unity photoluminescence quantum yield (PLQY). The gradient energy level of the shell reduced the hole injection barriers and increased the hole injection efficiency to balance the charge injection of LEDs. As a result, the LEDs achieved a high external quantum efficiency (EQE) of 22.83%, luminance of 111,319 cd/m2 and a long operational lifetime (T95@100 cd/m2) over 6,500 h, demonstrating the state-of-the-art performance for the CQW based LEDs.
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Chromatin modifications shape the epigenome and are essential for gene expression reprogramming during plant development and adaptation to the changing environment. Chromatin modification enzymes require primary metabolic intermediates such as S-adenosyl-methionine, acetyl-CoA, alpha-ketoglutarate, and NAD+ as substrates or cofactors. The availability of the metabolites depends on cellular nutrients, energy and reduction/oxidation (redox) states, and affects the activity of chromatin regulators and the epigenomic landscape. The changes in the plant epigenome and the activity of epigenetic regulators in turn control cellular metabolism through transcriptional and post-translational regulation of metabolic enzymes. The interplay between metabolism and the epigenome constitutes a basis for metabolic control of plant growth and response to environmental changes. This review summarizes recent advances regarding the metabolic control of plant chromatin regulators and epigenomes, which are involved in plant adaption to environmental stresses.
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Epigênese Genética , Epigenoma , Cromatina , OxirreduçãoRESUMO
BACKGROUND: Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. METHODS: Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). RESULTS: Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. CONCLUSIONS: This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.
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Transtornos Cronobiológicos , Relógios Circadianos , Colite Ulcerativa , Humanos , Colite Ulcerativa/genética , Relógios Circadianos/genética , Análise da Randomização Mendeliana , Comorbidade , Estudo de Associação Genômica Ampla , Peptidase 7 Específica de Ubiquitina , Proteínas ArgonautasRESUMO
Vascular calcification is a pathological process commonly associated with atherosclerosis, chronic kidney disease, and diabetes. Paraspeckle protein NONO is a multifunctional RNA/DNA binding protein involved in many nuclear biological processes but its role in vascular calcification remains unclear. Here, we observed that NONO expression was decreased in calcified arteries of mice and patients with CKD. We generated smooth muscle-specific NONO-knockout mice and established three different mouse models of vascular calcification by means of 5/6 nephrectomy, adenine diet to induce chronic kidney failure, or vitamin D injection. The knockout mice were more susceptible to the development of vascular calcification relative to control mice, as verified by an increased calcification severity and calcium deposition. Likewise, aortic rings from knockout mice showed more significant vascular calcification than those from control mice ex vivo. In vitro, NONO deficiency aggravated high phosphate-induced vascular smooth muscle cell osteogenic differentiation and apoptosis, whereas NONO overexpression had a protective effect. Mechanistically, we demonstrated that the regulation of vascular calcification by NONO was mediated by bone morphogenetic protein 2 (BMP2). NONO directly bound to the BMP2 promoter using its C-terminal region, exerting an inhibitory effect on the transcription of BMP2. Thus, our study reveals that NONO is a novel negative regulator of vascular calcification, which inhibits osteogenic differentiation of vascular smooth muscle cell and vascular calcification via negatively regulating BMP2 transcription. Hence, NONO may provide a promising target for the prevention and treatment of vascular calcification.
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Proteína Morfogenética Óssea 2 , Modelos Animais de Doenças , Camundongos Knockout , Músculo Liso Vascular , Miócitos de Músculo Liso , Osteogênese , Insuficiência Renal Crônica , Transcrição Gênica , Calcificação Vascular , Animais , Humanos , Masculino , Camundongos , Doenças da Aorta/genética , Doenças da Aorta/prevenção & controle , Doenças da Aorta/patologia , Doenças da Aorta/metabolismo , Apoptose/efeitos dos fármacos , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Regiões Promotoras Genéticas , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/prevenção & controle , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Calcificação Vascular/patologia , Calcificação Vascular/prevenção & controle , Calcificação Vascular/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/etiologiaRESUMO
Breast cancer (BC) is the fourth most prevalent cancer in China. Despite conventional treatment strategies, BC patients often have poor therapeutic outcomes, leading to significant global cancer mortality rates. Chimeric antigen receptor (CAR)-based immunotherapy is a promising and innovative approach for cancer treatment that redirects immune cells to attack tumor cells expressing selected tumor antigens (TAs). T cells, natural killer (NK) cells, and macrophages, key components of the immune system, are used in CAR-based immunotherapies. Although remarkable progress has been made with CAR-T cells in hematologic malignancies, the application of CAR-based immunotherapy to BC has lagged. This is partly due to obstacles such as tumor heterogeneity, which is further associated with the TA and BC subtypes, and the immunosuppressive tumor microenvironment (TME). Several combinatorial approaches, including the use of immune checkpoint inhibitors, oncolytic viruses, and antitumor drugs, have been proposed to overcome these obstacles in BC treatment. Furthermore, several CAR-based immunotherapies for BC have been translated into clinical trials. This review provides an overview of the recent progress in CAR-based immunotherapy for BC treatment, including targeting of TAs, consideration of BC subtypes, assessment of the TME, and exploration of combinatorial therapies. The authors focused on preclinical studies and clinical trials of CAR-T cells, CAR-NK cells, and CAR-macrophages especially conducted in China, followed by an internal comparison and discussion of current limits. In conclusion, this review elucidates China's contribution to CAR-based immunotherapies for BC and provides inspiration for further research. PLAIN LANGUAGE SUMMARY: Despite conventional treatment strategies, breast cancer (BC) patients in China often have poor therapeutic outcomes. Chimeric antigen receptor (CAR)-based immunotherapy, a promising approach, can redirect immune cells to kill tumor cells expressing selected tumor antigens (TAs). However, obstacles such as TA selection, BC subtypes, and immunosuppressive tumor microenvironment still exist. Therefore, various combinatorial approaches have been proposed. This article elucidates several Chinese CAR-based preclinical and clinical studies in BC treatment with comparisons of foreign research, and CAR-immune cells are analyzed, providing inspiration for further research.
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Neoplasias da Mama , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Feminino , Receptores de Antígenos Quiméricos/uso terapêutico , Neoplasias da Mama/terapia , Imunoterapia Adotiva , Neoplasias/terapia , Imunoterapia , Antígenos de Neoplasias , Microambiente TumoralRESUMO
CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.
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Antígenos CD7 , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Indução de Remissão , Humanos , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Adolescente , Pessoa de Meia-Idade , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Adulto Jovem , Criança , Recidiva , Transplante Homólogo , Receptores de Antígenos Quiméricos/uso terapêutico , Resultado do Tratamento , Pré-Escolar , Taxa de SobrevidaRESUMO
Novel functions and advanced structure, where each single component could not be produced individually, can exhibit from the collective and synergistic behavior of component systems. This synergetic strategy has been successfully demonstrated for co-assembly of polymer-polymer to construct hierarchical nanomaterials. However, differences in the natures of polymer and small molecules impose challenges in the construction of sophisticated co-assemblies with geometrical and compositional control. Herein, a synergetic self-assembly strategy is proposed to prepare organic-organic hybrid colloidal mesostructures by blending a liquid crystalline block copolymer (LC-BCP) with small molecular amphiphiles. Through a classic solvent-exchange process, amphiphiles embedded with LC-BCP realize multi-component nucleation and hierarchical assembly driven by anisotropic interaction from the LC ordering alignment of the core-forming block. 1D nanofibers with a periodic striped structure are formed by further LC component fusion and refinement. In addition, LC ordering effect of LC-BCP can be regulated by selecting appropriate solvents and leads to the formation of vesicular co-micelles. By means of the thermal-responsive behavior of amphiphiles, hexagonal pore arrays are finally generated on the surface of those vesicles.
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The development of pure-blue perovskite light-emitting diodes (PeLEDs) faces challenges of spectral stability and low external quantum efficiency (EQE) due to phase separation in mixed halide compositions. Perovskite quantum dots (QDs) with strong confinement effects are promising alternatives to achieve high-quality pure-blue PeLEDs, yet their performance is often hindered by the poor size distribution and high trap density. A strategy combining thermodynamic control with a polishing-driven ligand exchange process to produce high-quality QDs is developed. The strongly-confined pure-blue (≈470 nm) CsPbBr3 QDs exhibit narrow size distribution (12% dispersion) and are achieved in Br-rich ion environment based on growth thermodynamic control. Subsequent polishing-driven ligand exchange process removes imperfect surface sites and replaces initial long-chain organic ligands with short-chain benzene ligands. The resulting QDs exhibit high photoluminescence quantum yield (PLQY) to near-unity. The resulting PeLEDs exhibit a pure-blue electroluminescence (EL) emission at 472 nm with narrow full-width at half-maximum (FWHM) of 25 nm, achieving a maximum EQE of 10.7% and a bright maximum luminance of 7697 cd m-2. The pure-blue PeLEDs show ultrahigh spectral stability under high voltage, a low roll-off of EQE, and an operational half-lifetime (T50) of 127 min at an initial luminance of 103 cd m-2 under continuous operation.
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Ultrathin PtSe2 ribbons can host spin-polarized edge states and distinct edge electrocatalytic activity, emerging as a promising candidate for versatile applications in various fields. However, the direct synthesis is still challenging and the growth mechanism is still unclear. Herein, the arrayed growth of ultrathin PtSe2 ribbons on bunched vicinal Au(001) facets, via a facile chemical vapor deposition (CVD) route is reported. The ultrathin PtSe2 flakes can transform from traditional irregular shapes to desired ribbon shapes by increasing the height of bunched and unidirectionally oriented Au steps (with step height hstep) is found. This crossover, occurring at hstep ≈ 3.0 nm, defines the tailored growth from step-flow to single-terrace-confined modes, as validated by density functional theory calculations of the different system energies. On the millimeter-scale single-crystal Au(001) films with aligned steps, the arrayed ultrathin PtSe2 ribbons with tunable width of ≈20-1000 nm, which are then served as prototype electrocatalysts for hydrogen evolution reaction (HER) is achieved. This work should represent a huge leap in the direct synthesis and the mechanism exploration of arrayed ultrathin transition-metal dichalcogenides (TMDCs) ribbons, which should stimulate further explorations of the edge-related physical properties and practical applications.