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1.
Immunity ; 55(1): 159-173.e9, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-34982959

RESUMEN

To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.


Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Microglía/metabolismo , Mitocondrias/metabolismo , Convulsiones/inmunología , Animales , Conducta Animal , Susceptibilidad a Enfermedades , Sinapsis Eléctricas/metabolismo , Metabolismo Energético , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-33/genética , Ratones , Ratones Noqueados , Microglía/patología , Neurogénesis/genética , Proteína Oncogénica v-akt/metabolismo , Fagocitosis , Transducción de Señal
2.
Cell ; 166(6): 1500-1511.e9, 2016 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-27610572

RESUMEN

Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.


Asunto(s)
Linfocitos T CD8-positivos/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Animales , Linfocitos T CD8-positivos/inmunología , Sistemas CRISPR-Cas , Carcinogénesis/genética , Carcinogénesis/inmunología , Femenino , Factor de Transcripción GATA3/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Melanoma/inmunología , Melanoma/fisiopatología , Metalotioneína/deficiencia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
3.
Immunity ; 53(3): 658-671.e6, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32937153

RESUMEN

Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Glucocorticoides/metabolismo , Macrófagos/metabolismo , Melanoma Experimental/patología , Microambiente Tumoral/inmunología , Animales , Linfocitos T CD8-positivos/citología , Línea Celular Tumoral , Hematopoyesis/inmunología , Factor Nuclear 1-alfa del Hepatocito/biosíntesis , Inhibidores de Puntos de Control Inmunológico , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/inmunología
5.
Nat Immunol ; 14(7): 732-40, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23727894

RESUMEN

Transcription factors of the STAT family are critical in the cytokine-mediated functional differentiation of CD4(+) helper T cells. Signaling inhibitors of the SOCS family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by directly binding to the Il9 promoter. Our data thus demonstrate a critical role for CIS in controlling the proallergic generation of helper T cells.


Asunto(s)
Asma/inmunología , Inflamación/inmunología , Factores de Transcripción STAT/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/inmunología , Histocitoquímica , Immunoblotting , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , ARN/química , ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Proteínas Supresoras de la Señalización de Citocinas/genética
6.
Br J Cancer ; 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834745

RESUMEN

BACKGROUND: Diffuse invasion remains a primary cause of treatment failure in pediatric high-grade glioma (pHGG). Identifying cellular driver(s) of pHGG invasion is needed for anti-invasion therapies. METHODS: Ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG were subjected to isolation of matching pairs of invasive (HGGINV) and tumor core (HGGTC) cells. RESULTS: pHGGINV cells were intrinsically more invasive than their matching pHGGTC cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57+CD133- cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57+CD133- > CD57+CD133+ > CD57-CD133+ > CD57-CD133- cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57+CD133- cells in the HGGINV front (HGGINV/CD57+CD133- cells) mediated by NANOG and SHH over-expression. Direct implantation of CD57+ (CD57+/CD133- and CD57+/CD133+) cells into mouse brains reconstituted diffusely invasion, while depleting CD57+ cells (i.e., CD57-CD133+) abrogated pHGG invasion. CONCLUSION: We revealed significantly increased invasive capacities in HGGINV cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57+CD133- and CD57+CD133+ cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells.

7.
Trends Immunol ; 42(2): 165-175, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33446417

RESUMEN

Mammalian T cell development initiates from the migration of hematopoietic progenitors to the thymus, which undergo cell proliferation, T-lineage specification and commitment, as well as positive and negative selection. These processes are precisely controlled at multiple levels and have been intensively studied using gene-modified animal models and in vitro coculture systems. However, several long-standing questions, including the characterization of the rare but crucial progenitors/precursors and the molecular mechanisms underlying their fate decision, have been dampened because of cell scarcity and lack of appropriate techniques. Single-cell RNA sequencing (scRNA-seq) makes it possible to investigate and resolve some of these questions, leading to new remarkable progress in identifying and characterizing early thymic progenitors and delineating the refined developmental trajectories of conventional and unconventional T cells.


Asunto(s)
Células Madre Hematopoyéticas , Linfocitos T , Animales , Diferenciación Celular , Linaje de la Célula , Proliferación Celular , Análisis de Secuencia de ARN , Timo
8.
BMC Infect Dis ; 24(1): 506, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38773459

RESUMEN

BACKGROUND: The sharp increase in fungal infections, insufficient diagnostic and treatment capabilities for fungal infections, poor prognosis of patients with fungal infections as well as the increasing drug resistance of fungi are serious clinical problems. It is necessary to explore the implementation and evaluation methods of antifungal stewardship (AFS) to promote the standardized use of antifungal drugs. METHODS: The AFS programme was implemented at a tertiary first-class hospital in China using a plan-do-check-act (PDCA) quality management tool. A baseline investigation was carried out to determine the utilization of antifungal drugs in pilot hospitals, analyse the existing problems and causes, and propose corresponding solutions. The AFS programme was proposed and implemented beginning in 2021, and included various aspects, such as team building, establishment of regulations, information construction, prescription review and professional training. The management effectiveness was recorded from multiple perspectives, such as the consumption of antifungal drugs, the microbial inspection rate of clinical specimens, and the proportion of rational prescriptions. The PDCA management concept was used for continuous improvement to achieve closed-loop management. RESULTS: In the first year after the implementation of the AFS programme, the consumption cost, use intensity and utilization rate of antifungal drugs decreased significantly (P < 0.01). The proportion of rational antifungal drug prescriptions markedly increased, with the proportion of prescriptions with indications increasing from 86.4% in 2019 to 97.0% in 2022, and the proportion of prescriptions with appropriate usage and dosage increased from 51.9 to 87.1%. In addition, after the implementation of the AFS programme, physicians' awareness of the need to complete microbial examinations improved, and the number of fungal cultures and serological examinations increased substantially. Statistics from drug susceptibility tests revealed a decrease in the resistance rate of Candida to fluconazole. CONCLUSION: This study indicated that the combination of AFS and the PDCA cycle could effectively reduce antifungal consumption and promote the rational use of antifungal drugs, providing a reference for other health care systems to reduce the overuse of antifungal drugs and delay the progression of fungal resistance.


Asunto(s)
Antifúngicos , Programas de Optimización del Uso de los Antimicrobianos , Micosis , Centros de Atención Terciaria , Antifúngicos/uso terapéutico , Humanos , China , Micosis/tratamiento farmacológico , Micosis/microbiología , Farmacorresistencia Fúngica , Utilización de Medicamentos/normas , Utilización de Medicamentos/estadística & datos numéricos
9.
Nature ; 558(7710): 454-459, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29899446

RESUMEN

The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4+ T cells promotes autoimmunity, whereas sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer1,2. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.


Asunto(s)
Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Redes Reguladoras de Genes/genética , Melanoma/inmunología , Transcripción Genética , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Interleucina-27/inmunología , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Melanoma/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Proteínas Proto-Oncogénicas c-maf/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Reproducibilidad de los Resultados
10.
J Transl Med ; 21(1): 444, 2023 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-37415222

RESUMEN

BACKGROUND: Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM. MATERIALS AND METHODS: 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 1011 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage. RESULTS: PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times. CONCLUSION: A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Animales , Ratones , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos NOD , Ratones SCID , Modelos Animales de Enfermedad , Línea Celular Tumoral
11.
Semin Immunol ; 44: 101324, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31676122

RESUMEN

IL-10 is a critical immunoregulatory cytokine expressed in virtually all immune cell types. Maintaining a delicate balance between effective immune response and tolerance requires meticulous and dynamic control of IL-10 expression both epigenetically and transcriptionally. In this Review, we describe the epigenetic mechanisms controlling IL-10 expression, including chromatin remodeling, 3D chromatin loops, histone modification and DNA methylation. We discuss the role of transcription factors in directing chromatin modifications, with a special highlight on the emerging concept of pioneer transcription factors in setting up the chromatin landscape in T helper cells for IL-10 induction. Besides summarizing the recent progress on transcriptional regulation in specialized IL-10 producers such as type 1 regulatory T cells, regulatory B cells and regulatory innate lymphoid cells, we also discuss common transcriptional mechanisms for IL-10 regulation that are shared with other IL-10 producing cells.


Asunto(s)
Interleucina-10/genética , Animales , Cromatina/metabolismo , Metilación de ADN , Epigénesis Genética , Histonas/metabolismo , Humanos , Factores de Transcripción/metabolismo , Transcripción Genética
12.
Proc Natl Acad Sci U S A ; 117(36): 22237-22248, 2020 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-32839316

RESUMEN

NOD-like receptors (NLRs) are traditionally recognized as major inflammasome components. The role of NLRs in germ cell differentiation and reproduction is not known. Here, we identified the gonad-specific Nlrp14 as a pivotal regulator in primordial germ cell-like cell (PGCLC) differentiation in vitro. Physiologically, knock out of Nlrp14 resulted in reproductive failure in both female and male mice. In adult male mice, Nlrp14 knockout (KO) inhibited differentiation of spermatogonial stem cells (SSCs) and meiosis, resulting in trapped SSCs in early stages, severe oligozoospermia, and sperm abnormality. Mechanistically, NLRP14 promoted spermatogenesis by recruiting a chaperone cofactor, BAG2, to bind with HSPA2 and form the NLRP14-HSPA2-BAG2 complex, which strongly inhibited ChIP-mediated HSPA2 polyubiquitination and promoted its nuclear translocation. Finally, loss of HSPA2 protection and BAG2 recruitment by NLRP14 was confirmed in a human nonsense germline variant associated with male sterility. Together, our data highlight a unique proteasome-mediated, noncanonical function of NLRP14 in PGCLC differentiation and spermatogenesis, providing mechanistic insights of gonad-specific NLRs in mammalian germline development.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Diferenciación Celular/fisiología , Proteínas HSP70 de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Espermatogénesis/genética , Transporte Activo de Núcleo Celular/genética , Transporte Activo de Núcleo Celular/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Células Madre Germinales Adultas/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Femenino , Eliminación de Gen , Regulación de la Expresión Génica/fisiología , Variación Genética , Células Germinativas , Proteínas HSP70 de Choque Térmico/genética , Humanos , Infertilidad Masculina/genética , Masculino , Ratones , Chaperonas Moleculares/genética , Nucleósido-Trifosfatasa/genética , Nucleósido-Trifosfatasa/metabolismo , Espermatogénesis/fisiología
13.
Sensors (Basel) ; 23(16)2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37631718

RESUMEN

Aiming at the problem of large measurement error and phase shift in resistance voltage dividers under high-frequency conditions in the field of power measurement, such as power harmonics, an error correction method is proposed for an alternating current (AC) resistance voltage divider based on the equivalence principle. Firstly, the frequency error model of the AC resistance voltage divider precision is established, and the angle difference of the continuous spectrum ratio difference from 50 Hz to 100 kHz is corrected by determining the shielding structure and the resistance parameters and fine-tuning the shielding potential correction method to reduce the capacities error of the AC resistance voltage divider design precision. At the same time, the performance parameters such as the direction and magnitude of the shielding potential compensation capacitive error are investigated. Finally, the precision voltage divider (the maximum voltage applied is 480 V) calibration experiments verify that the important characteristic judgment factor of the voltage divider is independent of the frequency and the equivalent capacitance value, which effectively solves the phase correction problem of harmonic power measurement.

14.
Lab Invest ; 102(2): 185-193, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34802040

RESUMEN

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.


Asunto(s)
Neoplasias Encefálicas/terapia , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Adolescente , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/administración & dosificación , Benzamidas/farmacología , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Quimioradioterapia , Niño , Cisplatino/administración & dosificación , Terapia Combinada/métodos , Evaluación Preclínica de Medicamentos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Lactante , Masculino , Ratones Endogámicos NOD , Ratones SCID , Morfolinas/administración & dosificación , Morfolinas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Dosificación Radioterapéutica
15.
Eur J Nucl Med Mol Imaging ; 49(8): 2983-2993, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35543731

RESUMEN

PURPOSE: This study aimed to explore the clinical staging performance of [68 Ga]Ga-DOTA-FAPI-04 PET/CT compared with that of 2-[18F]FDG PET/CT in non-small cell lung cancer (NSCLC) patients lesion by lesion. METHODS: A total of 134 diagnosed or suspected NSCLC patients were enrolled in the prospective study (ChiCTR2000038080); they received paired 2-[18F]FDG PET/CT and [68 Ga]Ga-DOTA-FAPI-04 PET/CT. Of these patients, the retrospective analysis of 74 NSCLC patients with pathological results was conducted from primary tumor (T) diagnosis, lymph node (N), and metastatic lesion (M) staging. The imaging characteristics of the lung nodules and suspected metastases were obtained and analyzed, and the staging performance of 2-[18F]FDG PET/CT and [68 Ga]Ga-DOTA-FAPI-04 PET/CT was compared. RESULTS: For T diagnosis, [68 Ga]Ga-DOTA-FAPI-04 showed better diagnostic performance than 2-[18F]FDG in 79 lung nodules of 72 patients, especially for nonsolid and small-dimension adenocarcinoma nodules. For N staging, 98 lymph nodes (LNs) with pathological results in 37 patients were analyzed. The SUVmax of [68 Ga]Ga-DOTA-FAPI-04 in the nonmetastatic LNs was significantly lower than that in the metastatic LNs. Regarding metastatic LN identification, the calculated optimum cut-off value of [68 Ga]Ga-DOTA-FAPI-04 SUVmax was 5.5, and the diagnostic accuracy using [68 Ga]Ga-DOTA-FAPI-04 and 2-[18F]FDG criteria was 94% and 30%, respectively (P < 0.001). For M staging, [68 Ga]Ga-DOTA-FAPI-04 identified more lesions than 2-[18F]FDG (257 vs. 139 lesions) in 14 patients with multiple metastases. Overall, the staging accuracy of [68 Ga]Ga-DOTA-FAPI-04 was better than that of 2-[18F]FDG in 52 patients with different pathological stages [43/52 (82.7%) vs. 27/52 (51.9%), P = 0.001]. CONCLUSION: Compared with 2-[18F]FDG PET/CT, [68 Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated better staging performance in NSCLC patients with different pathological stages, especially those with localized disease.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Fluorodesoxiglucosa F18 , Compuestos Heterocíclicos con 1 Anillo , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Quinolinas , Estudios Retrospectivos
16.
Transpl Infect Dis ; 24(5): e13924, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36254516

RESUMEN

BACKGROUND: Current methods for benchmarking inpatient antimicrobial use (AU) could benefit from combining AU with antimicrobial resistance (AR) information to provide metrics benchmarked to microbiological data; this may yield more instructive and better risk-adjusted measurements than AU and AR in isolation. METHODS: In this retrospective single-center study, we computed facility-wide AU/AR ratios from 2019 to 2020 for specific antimicrobial agents and corresponding AR events, and compared median monthly AU/AR ratios between March 2019 through December 2019 (pre-COVID period) and March 2020 through December 2020 (COVID period). Aggregate AU was expressed as a ratio to aggregate AR events for antimicrobials that typically have activity against the AR organism and are frequently used to treat the AR organism in clinical practice. We also computed AU/AR ratios in our surgical intensive care unit in the pre-COVID period. RESULTS: High-median facility-wide monthly AU/AR ratios were observed for intravenous vancomycin/methicillin-resistant Staphylococcus aureus, with 130.0 in the pre-COVID period and 121.3 in the COVID period (p =.520). Decreases in facility-wide median monthly AU/AR ratios were observed between periods for meropenem/ESBL Enterobacterales (20.9 vs. 7.9, p < .001), linezolid/vancomycin-resistant Enterococcus (48.5 vs. 15.8, p =.004), and daptomycin/vancomycin-resistant Enterococcus (32.2 vs. 4.8, p = .002). Increases in facility-wide median monthly AU/AR ratios were observed between periods for ceftazidime-avibactam/carbapenem-resistant Enterobacterales (0.0 vs. 3.2, p = .020) and ceftazidime-avibactam/multidrug-resistant Pseudomonas aeruginosa (0.0 vs. 4.0, p = .017). The AU/AR ratio for intravenous vancomycin/methicillin-resistant S. aureus in the surgical intensive care unit was 191.5 in the pre-COVID period. CONCLUSIONS: AU/AR ratios may be used to supplement current AU and AR metrics. Future directions should include the development of more AU metrics benchmarked to microbiological information. AU metrics more specific to transplant infectious diseases should be developed.


Asunto(s)
Antiinfecciosos , Tratamiento Farmacológico de COVID-19 , Daptomicina , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Benchmarking , Carbapenémicos , Atención a la Salud , Farmacorresistencia Bacteriana , Farmacorresistencia Bacteriana Múltiple , Humanos , Pacientes Internos , Linezolid , Meropenem , Pruebas de Sensibilidad Microbiana , Estudios Retrospectivos , Vancomicina
17.
J Vis ; 22(10): 13, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-36107125

RESUMEN

Traditional visual search tasks in the laboratories typically involve looking for targets in 2D displays with exemplar views of objects. In real life, visual search commonly entails 3D objects in 3D spaces with nonperpendicular viewing and relative motions between observers and search array items, both of which lead to transformations of objects' projected images in lawful but unpredicted ways. Furthermore, observers often do not have to memorize a target before searching, but may refer to it while searching, for example, holding a picture of someone while looking for them from a crowd. Extending the traditional visual search task, in this study, we investigated the effects of image transformation as a result of perspective change yielded by discrete viewing angle change (Experiment 1) or continuous rotation of the search array (Experiment 2) and of having external references on visual search performance. Results showed that when searching from 3D objects with a non-zero viewing angle, performance was similar to searching from 2D exemplar views of objects; when searching for 3D targets from rotating arrays in virtual reality, performance was similar to searching from stationary arrays. In general, discrete or continuous perspective change did not affect the search outcomes in terms of accuracy, response time, and self-rated confidence, or the search process in terms of eye movement patterns. Therefore, visual search does not require the exact match of retinal images. Additionally, being able to see the target during the search improved search accuracy and observers' confidence. It increased search time because, as revealed by the eye movements, observers actively checked back on the reference target. Thus, visual search is an embodied process that involves real-time information exchange between the observers and the environment.


Asunto(s)
Atención , Percepción Visual , Atención/fisiología , Movimientos Oculares , Humanos , Tiempo de Reacción/fisiología , Percepción Visual/fisiología
18.
Sensors (Basel) ; 22(7)2022 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-35408165

RESUMEN

Advanced sensing and measurement technology is the key to realizing the transparent power grid and electric internet of things. Meanwhile, sensors, as an indispensable part of the smart grid, can monitor, collect, process, and transmit various types of data information of the power system in real-time. In this way, it is possible to further control the power system. Among them, partial discharge (PD) sensors are of great importance in the fields of online monitoring of insulation condition, intelligent equipment control, and power maintenance of power systems. Therefore, this paper intends to focus on advanced sensing materials and study new materials for the improvement for partial discharge sensors. As two-dimensional material, graphene is introduced. The electromagnetic properties of graphene partial discharge sensor electrode plate material are analyzed theoretically. By studying the influence of different chemical potential, relaxation time, temperature, and frequency, we obtain the changing curve of conductivity, dielectric constant, and refractive index. A linear regression model based on the least-squares method was developed for the three electromagnetic properties. Finally, the simulation and experiment verified that the graphene partial discharge sensor has better absorption of the partial discharge signal. This study can apply to the design of graphene partial discharge sensors.

19.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-36012319

RESUMEN

EAR (Ethylene-responsive element binding factor-associated Amphiphilic Repression) motif-containing transcription repressors have been shown to regulate plant growth and development, and plant responses to plant hormones and environmental stresses including biotic and abiotic stresses. However, the functions of most EAR-motif-containing proteins remain largely uncharacterized. The plant hormone abscisic acid (ABA) also plays important roles in regulating plant responses to abiotic stresses via activation/repression of ABA-responsive genes. We report here the identification and functional characterization of two ABA-responsive EAR motif-containing protein genes, AtEAU1 (Arabidopsis thaliana EAR motif-containing ABAUp-regulated 1) and AtEAU2. Quantitative RT-PCR results show that the expressions of AtEAU1 and AtEAU2 were increased by ABA treatment, and were decreased in the ABA biosynthesis mutant aba1-5. Assays in transfected Arabidopsis protoplasts show that both AtEAU1 and AtEAU2 were specifically localized in the nucleus, and when recruited to the promoter region of the reporter gene by a fused DNA binding domain, repressed reporter gene expression. By using T-DNA insertion mutants and a gene-edited transgene-free mutant generated by CRISPR/Cas9 gene editing, we performed ABA sensitivity assays, and found that ABA sensitivity in the both ateau1 and ateau2 single mutants was increased in seedling greening assays. ABA sensitivity in the ateau1 ateau2 double mutants was also increased, but was largely similar to the ateau1 single mutants. On the other hand, all the mutants showed a wild type response to ABA in root elongation assays. Quantitative RT-PCR results show that the expression level of PYL4, an ABA receptor gene was increased, whereas that of ABI2, a PP2C gene was decreased in the ateau1 and ateau1 single, and the ateau1 ateau2 double mutants. In summary, our results suggest that AtEAU1 and AtEAU2 are ABA-response genes, and AtEAU1 and AtEAU2 are novel EAR motif-containing transcription repressors that negatively regulate ABA responses in Arabidopsis, likely by regulating the expression of some ABA signaling key regulator genes.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacología , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Mutación , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Factores de Transcripción/metabolismo
20.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(1): 35-42, 2022 Jan.
Artículo en Zh | MEDLINE | ID: mdl-35048597

RESUMEN

OBJECTIVE: To induce the development of tertiary lymphoid organs (TLO) in a mouse model of melanoma and to evaluate TLO's functions in antitumor immunity. METHODS: Lymphotoxin-beta receptor (LTßR) was overexpressed in NIH3T3 cells through the lentivirus system and the overexpression efficiency of LTßR in LTßR-NIH3T3 cells was examined. Western blot and qPCR were used to examine the non-canonical nuclear factor (NF)-κB signaling pathway in NIH3T3 cells overexpressing LTßR. B16-OVA melanoma mouse model was constructed to explore the induction of TLO and anti-tumor functions of TLO in LTßR-NIH3T3 cells. RESULTS: LTßR was overexpressed in NIH3T3 cells through the lentivirus system, and flow cytometry showed that the proportion of GFP + cells reached 99%. The overexpression of LTßR activated the non-canonical NF-κB signaling pathway in NIH3T3 cells. Findings from the mouse tumor model suggest that the injection of LTßR-NIH3T3 cells successfully induced the development of lymphoid tissue around the tumor and enhanced the tumor infiltration of T cells and MHCⅡ + macrophages, significantly inhibiting tumor growth and prolonging the survival of tumor-bearing mice. CONCLUSION: LTßR-NIH3T3 cells promoted anti-tumor immunity by inducing TLO development, which may provide new perspectives for tumor immunotherapy.


Asunto(s)
Receptor beta de Linfotoxina , FN-kappa B , Animales , Macrófagos/metabolismo , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Células 3T3 NIH , Transducción de Señal
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