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A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.
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Neoplasias Encefálicas/fisiopatologia , Progressão da Doença , Glioma/fisiopatologia , Sinapses/patologia , Animais , Neoplasias Encefálicas/ultraestrutura , Modelos Animais de Doenças , Glioma/ultraestrutura , Humanos , Camundongos , Microscopia Eletrônica de Transmissão , Neurônios/fisiologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismoRESUMO
Carbon allocation has been fundamental for long-lived trees to survive cold stress at their upper elevation range limit. Although carbon allocation between non-structural carbohydrate (NSC) storage and structural growth is well-documented, it still remains unclear how ongoing climate warming influences these processes, particularly whether these two processes will shift in parallel or respond divergently to warming. Using a combination of an in situ downward-transplant warming experiment and an ex situ chamber warming treatment, we investigated how subalpine fir trees at their upper elevation limit coordinated carbon allocation priority among different sinks (e.g., NSC storage and structural growth) at whole-tree level in response to elevated temperature. We found that transplanted individuals from the upper elevation limit to lower elevations generally induced an increase in specific leaf area, but there was no detected evidence of warming effect on leaf-level saturated photosynthetic rates. Additionally, our results challenged the expectation that climate warming will accelerate structural carbon accumulation while maintaining NSC constant. Instead, individuals favored allocating available carbon to NSC storage over structural growth after 1 year of warming, despite the amplification in total biomass encouraged by both in situ and ex situ experimental warming. Unexpectedly, continued warming drove a regime shift in carbon allocation priority, which was manifested in the increase of NSC storage in synchrony to structural growth enhancement. These findings imply that climate warming would release trees at their cold edge from C-conservative allocation strategy of storage over structural growth. Thus, understanding the strategical regulation of the carbon allocation priority and the distinctive function of carbon sink components is of great implication for predicting tree fate in the future climate warming.
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Abies , Árvores , Humanos , Clima , Fotossíntese , CarbonoRESUMO
Atherosclerosis and atherothrombosis, the major contributors to cardiovascular diseases (CVDs), represent the leading cause of death worldwide. Current pharmacological therapies have been associated with side effects or are insufficient at halting atherosclerotic progression effectively. Pioneering work harnessing the passive diffusion or endocytosis properties of nanoparticles and advanced biotechnologies in creating recombinant proteins for site-specific delivery have been utilized to overcome these limitations. Since CVDs are complex diseases, the most challenging aspect of developing site-specific therapies is the identification of an individual and unique antigenic epitope that is only expressed in lesions or diseased areas. This review focuses on the pathological mechanism of atherothrombosis and discusses the unique targets that are important during disease progression. We review recent advances in site-specific therapy using novel targeted drug-delivery and nanoparticle-carrier systems. Furthermore, we explore the limitations and future perspectives of site-specific therapy for CVDs.
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Aterosclerose , Doenças Cardiovasculares , Nanopartículas , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Preparações FarmacêuticasRESUMO
Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
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Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Junções Comunicantes/metabolismo , Animais , Astrocitoma/metabolismo , Astrocitoma/radioterapia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Comunicação Celular/efeitos da radiação , Morte Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Extensões da Superfície Celular/metabolismo , Extensões da Superfície Celular/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Conexina 43/metabolismo , Progressão da Doença , Proteína GAP-43/metabolismo , Junções Comunicantes/efeitos da radiação , Glioma/metabolismo , Glioma/patologia , Glioma/radioterapia , Humanos , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Tolerância a Radiação/efeitos dos fármacosRESUMO
DNA-double strand break (DSB), detected by immunostaining of key proteins orchestrating repair, like γH2AX and 53BP1, is well established as a surrogate for tissue radiosensitivity. We hypothesized that the generation of normal brain 3D organoids ("mini-brains") from human induced pluripotent stem cells (hiPSC) combined with detection of DNA damage repair (DDR) may hold the promise towards developing personalized models for the determination of normal tissue radiosensitivity. In this study, cerebral organoids, an in vitro model that stands in its complexity between 2D cellular system and an organ, have been used. To quantify radiation-induced response, immunofluorescent staining with γH2AX and 53BP1 were applied at early (30 min, initial damage), and late time points (18 and 72 h, residual damage), following clinical standard 2 Gy irradiation. Based on our findings, assessment of DDR kinetics as a surrogate for radiosensitivity in hiPSC derived cerebral organoids is feasible. Further development of mini-brains recapitulating mature adult neuronal tissue and implementation of additional signaling and toxicity surrogates may pave the way towards development of next-generation personalized assessment of radiosensitivity in healthy neuronal tissue.
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Encéfalo/citologia , Dano ao DNA , Organoides/citologia , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Células Cultivadas , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos da radiação , Técnicas de Cultura de Órgãos , Organoides/metabolismo , Organoides/efeitos da radiação , Doses de Radiação , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismoRESUMO
Endothelins (EDNs) and their receptors (EDNRs) are reported to be involved in the regulation of many physiological/pathological processes, such as cardiovascular development and functions, pulmonary hypertension, neural crest cell proliferation, differentiation and migration, pigmentation, and plumage in chickens. However, the functionality, signaling, and tissue expression of avian EDN-EDNRs have not been fully characterized, thus impeding our comprehensive understanding of their roles in this model vertebrate species. Here, we reported the cDNAs of three EDN genes (EDN1, EDN2, EDN3) and examined the functionality and expression of the three EDNs and their receptors (EDNRA, EDNRB and EDNRB2) in chickens. The results showed that: 1) chicken (c-) EDN1, EDN2, and EDN3 cDNAs were predicted to encode bioactive EDN peptides of 21 amino acids, which show remarkable degree of amino acid sequence identities (91-95%) to their respective mammalian orthologs; 2) chicken (c-) EDNRA expressed in HEK293 cells could be preferentially activated by chicken EDN1 and EDN2, monitored by the three cell-based luciferase reporter assays, indicating that cEDNRA is a functional receptor common for both cEDN1 and cEDN2. In contrast, both cEDNRB and cEDNRB2 could be activated by all three EDN peptides with similar potencies, indicating that both receptors can function as common receptors for the three EDNs and share functional similarity. Moreover, activation of three EDNRs could stimulate intracellular calcium, MAPK/ERK, and cAMP/PKA signaling pathways. 3) qPCR assay revealed that cEDNs and cEDNRs are widely, but differentially, expressed in adult chicken tissues. Taken together, our data establishes a clear molecular basis to uncover the physiological/pathological roles of EDN-EDNR system in birds and helps to reveal the conserved actions of EDN-EDNR signaling across vertebrates.
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Galinhas/metabolismo , Endotelinas/metabolismo , Receptores de Endotelina/metabolismo , Sequência de Aminoácidos , Animais , Endotelinas/química , Endotelinas/genética , Feminino , Células HEK293 , Humanos , Masculino , Receptores de Endotelina/química , Transdução de Sinais , Distribuição TecidualRESUMO
Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.
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Ansiedade/fisiopatologia , Neuropeptídeos/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de Ocitocina/fisiologia , Animais , Transporte Axonal , Proteínas de Bactérias/análise , Sinalização do Cálcio/fisiologia , Dependovirus/genética , Comportamento Exploratório/efeitos dos fármacos , Genes Reporter , Vetores Genéticos , Proteínas Luminescentes/análise , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/farmacologia , Ocitocina/agonistas , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Neuropeptídeos/efeitos dos fármacos , Receptores de Neuropeptídeos/fisiologia , Receptores de Ocitocina/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos , Proteína Vermelha FluorescenteRESUMO
Malignant gliomas are the most common primary brain tumors, and are associated with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient production of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are associated with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-positive perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorgenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and molecular pathogenesis of primary brain tumors.
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Neoplasias Encefálicas/patologia , Glioma/patologia , Neurônios/citologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Células-Tronco/citologia , Envelhecimento , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Expressão Gênica , Genes p53/genética , Glioma/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Neovascularização Patológica/fisiopatologia , Neurogênese , Neurônios/patologia , Receptores Citoplasmáticos e Nucleares/genética , Células-Tronco/patologiaRESUMO
A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T->A mutations in the transmembrane domain of the Neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas remains enigmatic. We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one. T:A->A:T and T:A->C:G mutations, which are typical for ENU-induced mutagenesis, were predominant (41% to 55% of all somatic single nucleotide mutations). T->A mutations were identified in all five rat gliomas at Braf codon 545 (V545E), which corresponds to the human BRAF V600E. Additional screening revealed that 33 gliomas in BDIV rats and 12 gliomas in BDIX rats all carried a Braf V545E mutation, whereas peritumoral brain tissue of either strain had the wild-type sequence. The gliomas were immunoreactive to BRAF V600E antibody. These results indicate that Braf mutation is a frequent early event in the development of rat gliomas caused by a single dose of ENU.
Assuntos
Etilnitrosoureia/efeitos adversos , Glioma/genética , Neurilemoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Substituição de Aminoácidos , Animais , Genótipo , Glioma/induzido quimicamente , Mutagênese , Neurilemoma/induzido quimicamente , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/metabolismo , Ratos , Análise de Sequência de DNARESUMO
The lutetium containing nitride apatite Lu5(SiO4)3N was prepared by a solid state reaction at high temperature for the first time. Rietveld refinement indicated that the Lu5(SiO4)3N compound has a hexagonal space group of P63/m with cell parameters a = b = 9.700 Å and c = 7.238 Å. Additionally, the results revealed that there are two distinct lutetium sites in the Lu5(SiO4)3N host lattice, i.e. a Lu(1) site with nine coordination (Wyckoff site 4f) and a Lu(2) site with seven coordination (Wyckoff site 6h). Furthermore, the ratio of the number of Lu atoms in Lu(1) and Lu(2) sites is 3 : 2. The band gap for Lu5(SiO4)3N was determined to be 4.12 eV based on the density functional theory (DFT). In the Ce(3+) doped Lu5(SiO4)3N:0.03Ce(3+) compound, the emission peak centered at 462 nm was observed with the Commission International de I'Eclairage (CIE) coordinates of (0.148, 0.184), indicating blue-emission. Remarkably, in Ce(3+) and Tb(3+) co-doped Lu4.97-y(SiO4)3N:0.03Ce(3+),yTb(3+) compounds, the color-tunability was observed with increasing Tb(3+) co-doping rate on moving from blue at Tb(3+) = 0.00 to green at Tb = 0.09, due to the energy transfer from Ce(3+) to Tb(3+) ions being matched well with the decay curve results. Under the excitation at 359 nm, the absolute quantum efficiency (QE) for Lu5(SiO4)3N:0.03Ce(3+) was determined to be 42.13%. This phosphor material could be a platform for modeling a new phosphor and application in the solid-state lighting field.
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Utilizing cell membranes from diverse cell types for biointerfacing has demonstrated significant advantages in enhancing colloidal stability and incorporating biological properties, tailored specifically for various biomedical applications. However, the structures of these materials, particularly emulsions interfaced with red blood cell (RBC) or platelet (PLT) membranes, remain an underexplored area. This study systematically employs small- and ultra-small-angle neutron scattering (SANS and USANS) with contrast variation to investigate the structure of emulsions containing perfluorohexane within RBC (RBC/PFH) and PLT membranes (PLT/PFH). The findings reveal that the scattering length density of RBC and PLT membranes is 1.5 × 10-6 Å-2, similar to 30% (w/w) deuterium oxide. Using this solvent as a cell membrane-matching medium, estimated droplet diameters are 770 nm (RBC/PFH) and 1.5 µm (PLT/PFH), based on polydispersed sphere model fitting. Intriguingly, calculated patterns and invariant analysis reveal native droplet architectures featuring entirely liquid PFH cores, differing significantly from the observed bubble-droplet core system in electron microscopy. This highlights the advantage of SANS and USANS in differentiating genuine colloidal structures in complex dispersions. In summary, this work underscores the pivotal role of SANS and USANS in characterizing biointerfaced colloids and in uncovering novel colloidal structures with significant potential for biomedical applications and clinical translation.
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Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.
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Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.
Assuntos
Neoplasias da Mama , Fibroblastos Associados a Câncer , Sirtuínas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/patologia , Fibroblastos/patologia , Microambiente Tumoral , Proteínas de Ligação a DNA , Ubiquitina-Proteína Ligases , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMO
Two-dimensional nanomaterials hold great promise as electrode materials for the construction of excellent electrochemical energy storage and transformation apparatuses. In the study, metallic layered cobalt sulfide was, firstly, applied to the area of energy storage as a supercapacitor electrode. By a facile and scalable method for cathodic electrochemical exfoliation, metallic layered cobalt sulfide bulk can be exfoliated into high-quality and few-layered nanosheets with size distributions in the micrometer scale range and thickness in the order of several nanometers. With a two-dimensional thin sheet structure of metallic cobalt sulfide nanosheets, not only was a larger active surface area created, but also, the insertion/extraction of ions in the procedure of charge and discharge were enhanced. The exfoliated cobalt sulfide was applied as a supercapacitor electrode with obvious improvement compared with the original sample, and the specific capacitance increased from 307 Fâg-1 to 450 Fâg-1 at the current density of 1 Aâg-1. The capacitance retention rate of exfoliated cobalt sulfide enlarged to 84.7% from the original 81.9% of unexfoliated samples while the current density multiplied by 5 times. Moreover, a button-type asymmetric supercapacitor assembled using exfoliated cobalt sulfide as the positive electrode exhibits a maximum specific energy of 9.4 Whâkg-1 at the specific power of 1520 Wâkg-1.
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Astrocytoma and glioblastoma (GB) are reclassified subtypes of adult diffuse gliomas based on distinct isocitrate dehydrogenase (IDH) mutation in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The recurrence of gliomas is a common and inevitable challenge, and analyzing the distinct genomic alterations in astrocytoma and GB could provide insights into their progression. This study conducted a longitudinal investigation, utilizing whole-exome sequencing, on 65 paired primary/recurrent gliomas. It examined chromosome arm aneuploidies, copy number variations (CNVs) of cancer-related genes and pathway enrichments during the relapse. The veracity of these findings was verified through the integration of our data with multiple public resources and by corroborative immunohistochemistry (IHC). The results revealed a greater prevalence of aneuploidy changes and acquired CNVs in recurrent lower grade astrocytoma than in relapsed grade 4 astrocytoma and GB. Larger aneuploidy changes were predictive of an unfavorable prognosis in lower grade astrocytoma (P < 0.05). Further, patients with acquired gains of 1q, 6p or loss of 13q at recurrence had a shorter overall survival in lower grade astrocytoma (P < 0.05); however, these prognostic effects were confined in grade 4 astrocytoma and GB. Moreover, acquired gains of 12 genes (including VEGFA) on 6p during relapse were associated with unfavorable prognosis for lower grade astrocytoma patients. Notably, elevated VEGFA expression during recurrence corresponded to poorer survival, validated through IHC and CGGA data. To summarize, these findings offer valuable insights into the progression of gliomas and have implications for guiding therapeutic approaches during recurrence.
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The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1-PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses.
Assuntos
Antígeno B7-H1 , Proteínas com Domínio MARVEL , Proteínas da Mielina , Neoplasias , Linfócitos T , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Imunidade , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Linfócitos T/imunologia , Proteínas da Mielina/metabolismo , Proteínas com Domínio MARVEL/metabolismoRESUMO
Whitlockite has the advantages of a low sintering temperature, high stability, and a low fabrication cost, and it is widely used as the host for luminescent material. In this study, Ca1.8Li0.6La0.6-x(PO4)2:xDy3+ phosphor was prepared by the high-temperature solid-state method, and its structure, composition, and luminescence properties were systematically studied. The results showed that a new whitlockite type matrix was prepared by replacing Ca2+ in whitlockite with monovalent and trivalent cations. The prepared phosphors belonged to a hexagonal crystal system with a particle size in the range of 5-20 µm. Under the excitation of 350 nm UV light, the samples emitted white light, and there were mainly two stronger emission peaks at 481 nm in the blue band and 573 nm in the yellow band, which correspond to the electron transitions at 4F9/2â6H15/2 and 4F9/2â6H13/2 of Dy3+, respectively. The optimal doping concentration of Dy3+ in Ca1.8Li0.6La0.6(PO4)2 matrix was 0.03 (mol%). The main mechanism of concentration quenching in the sample was dipole-dipole energy transfer. When the temperature was 130 °C, the luminescence intensity of the samples was 78.7% of that at 30 °C, and their thermal quenching activation energy was 0.25 eV. The CIE coordinates of the sample at 30 °C were (0.2750, 0.3006), and their luminescent colors do not change with temperature. All the results indicate that Ca1.8Li0.6La0.6-x(PO4)2:xDy3+ phosphor is a luminescent material with good luminescence performance and thermal stability, which shows a promising application in the field of LED display.
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Ba2La2.85-x Tb0.15Sm x (SiO4)3F (BLSOF:0.15Tb3+,xSm3+) is a polychromatic phosphor with an apatite structure that was manufactured through a solid-state process. X-ray diffraction (XRD) and a scanning electron microscope (SEM) were utilized to examine the phosphor's phase and morphology. Using the Rietveld technique, the as-prepared phosphor structure was validated. By progressively raising the doping contents of the samarium, the phosphors emitted multicoloured luminescence from short to long wavelengths as indicated by analysis of the optical performance. Overall, the data provide strong evidence that the transfer of energy in BLSOF:0.15Tb3+,xSm3+ is responsible for the phosphor's colour-tunable property.
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The polychromatic phosphor with an apatite structure Ca2La3(SiO4)3F:0.15Tb3+,xSm3+ (CLSOF:0.15Tb3+,xSm3+) was synthesized via a solid-state route. The phase and morphology of the phosphor has been investigated by means of X-ray diffraction (XRD) and scanning electron microscopy (SEM). The structures of the as-prepared phosphor were verified by means of the Rietveld method. The optical performance was investigated thoroughly and the phosphors could emit multicolor light from short wavelengths to long wavelengths by gradually increasing the doping contents of samarium. All the results support that the energy transfer in CLSOF:0.15Tb3+,xSm3+ contributes to the color tunable property of the phosphor.
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Electroreduction of N2 is a highly promising route for NH3 production. The lack of efficient catalysts that can activate and then reduce N2 into NH3 limits this as a pragmatic application. In this work, a 2D layered group IV-V material, silicon phosphide (SiP), is evaluated as a suitable substrate for the electrochemical nitrogen reduction reaction (ENRR). To capture N2, one phosphorus (P) defect was introduced on the plane of SiP. DFT calculations found that the defective SiP monolayer (D1-SiP, which is defined by the P-defect on SiP) exhibits enormous prospects towards the ENRR because of enhanced electron conductivity, good activation on N2, lower limiting potential (UL = -0.87 V) through the enzymatic pathway, smooth charge transfer between the catalyst and the reaction species, and robust thermal stability. Importantly, D1-SiP demonstrates the suppressed activities on producing of H2 and N2H4 side-products. This research demonstrates the potential of 2D metal-free Si-based catalysts for nitrogen fixation and further enriches the study of group IV-V materials for the ENRR.