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1.
EMBO J ; 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39261664

RESUMEN

In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion.

2.
BMC Cardiovasc Disord ; 24(1): 500, 2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39294617

RESUMEN

BACKGROUND: This study aims to assess the associations of admission systolic blood pressure (SBP) level with spontaneous reperfusion (SR) and long-term prognosis in ST-elevation myocardial infarction (STEMI) patients. METHODS: Data from 3809 STEMI patients who underwent primary percutaneous coronary intervention within 24 h, as recorded in the Chinese STEMI PPCI Registry (NCT04996901), were analyzed. The primary endpoint was SR, defined as thrombolysis in myocardial infarction grade 2-3 flow of IRA according to emergency angiography. The second endpoint was 2-year all-cause mortality. The association between admission BP and outcomes was evaluated using Logistic regression or Cox proportional hazards models with restricted cubic splines, adjusting for clinical characteristics. RESULTS: Admission SBP rather than diastolic BP was associated with SR after adjustment. Notably, this relationship exhibits a nonlinear pattern. Below 120mmHg, There existed a significant positive correlation between admission SBP and the incidence of SR (adjusted OR per 10-mmHg decrease for SBP ≤ 120 mm Hg: 0.800; 95% CI: 0.706-0.907; p<0.001); whereas above 120mmHg, no further improvement in SR was observed (adjusted OR per 10-mmHg increase for SBP >120 mm Hg: 1.019; 95% CI: 0.958-1.084, p = 0.552). In the analysis of the endpoint event of mortality, patients admitted with SBP ranging from 121 to 150 mmHg exhibited the lowest mortality compared with those SBP ≤ 120mmHg (adjusted HR: 0.653; 95% CI: 0.495-0.862; p = 0.003). In addition, subgroups analysis with Killip class I-II showed SBP ≤ 120mmHg was still associated with increased risk of mortality. CONCLUSION: The present study revealed admission SBP above 120 mmHg was associated with higher SR,30-d and 2-y survival rate in STEMI patients. The admission SBP could be a marker to provide clinical assessment and treatment. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04996901), 07/27/2021.


Asunto(s)
Presión Sanguínea , Admisión del Paciente , Intervención Coronaria Percutánea , Sistema de Registros , Infarto del Miocardio con Elevación del ST , Humanos , Infarto del Miocardio con Elevación del ST/mortalidad , Infarto del Miocardio con Elevación del ST/terapia , Infarto del Miocardio con Elevación del ST/fisiopatología , Infarto del Miocardio con Elevación del ST/diagnóstico , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Anciano , Factores de Tiempo , China/epidemiología , Intervención Coronaria Percutánea/mortalidad , Intervención Coronaria Percutánea/efectos adversos , Factores de Riesgo , Resultado del Tratamiento , Medición de Riesgo , Circulación Coronaria
3.
BMC Med Educ ; 24(1): 32, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38183036

RESUMEN

BACKGROUND: Virtual simulation and face-to-face simulation are effective for clinical judgment training. Rare studies have tried to improve clinical judgment ability by applying virtual simulation and face-to-face simulation together. This study aimed to evaluate the effect of an integrated non-immersive virtual simulation and high-fidelity face-to-face simulation program on enhancing nursing students' clinical judgment ability and understanding of nursing students' experiences of the combined simulation. METHODS: A sequential exploratory mixed-methods study was conducted in a nursing simulation center of a university in Central China. Third-year nursing students (n = 122) taking clinical training in ICUs were subsequentially assigned to the integrated non-immersive virtual simulation and high-fidelity face-to-face simulation program arm (n = 61) or the face-to-face simulation-only arm (n = 61) according to the order in which they entered in ICU training. Clinical judgment ability was measured by the Lasater Clinical Judgment Rubric (LCJR). Focus group interviews were conducted to gather qualitative data. RESULTS: Students in both arms demonstrated significant improvement in clinical judgment ability scores after simulation, and students in the integrated arm reported more improvement than students in the face-to-face simulation-only arm. The qualitative quotes provided a context for the quantitative improvement measured by the LJCR in the integrated arm. Most of the quantitative findings were confirmed by qualitative findings, including the domains and items in the LJCR. The findings verified and favored the effect of the combination of non-immersive virtual simulation and high-fidelity face-to-face simulation integrated program on enhancing nursing students' clinical judgment ability. CONCLUSIONS: The integrated virtual simulation and face-to-face simulation program was feasible and enhanced nursing students' self-reported clinical judgment ability. This integrated non-immersive virtual simulation and high-fidelity face-to-face simulation program may benefit nursing students and newly graduated nurses in the ICU more than face-to-face simulation only.


Asunto(s)
Bachillerato en Enfermería , Estudiantes de Enfermería , Humanos , Juicio , China , Razonamiento Clínico
4.
Int J Clin Pract ; 2023: 6615789, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37153692

RESUMEN

Background: This study aimed to determine the effect of body mass index (BMI) on bone turnover markers in girls with idiopathic central precocious puberty (ICPP) according to weight status at diagnosis. Methods: Two hundred and eleven girls with ICPP were divided according to their weight status at diagnosis into three groups: normal weight, overweight, and obese. The serum levels of total procollagen type 1 N-terminal propeptide (P1NP), N-terminal midfragment of osteocalcin, ß-C-terminal telopeptide of type 1 collagen, and some biochemical indicators were measured. Associations between variables were evaluated by multiple regression analysis. Results: Serum P1NP concentrations were significantly different among groups (p < 0.001). No other significant differences were noted in N-terminal midfragment of osteocalcin and ß-C-terminal telopeptide of type 1 collagen. BMI was associated with estradiol (r = 0.155, p < 0.05) and inversely associated with P1NP (r = -0.251, p < 0.01), luteinizing hormone peak (r = -0.334, p < 0.01), follicle-stimulating hormone peak (r = -0.215, p < 0.01), and luteinizing hormone/follicle-stimulating hormone peak (r = -0.284, p < 0.01). Multiple regression analysis of factors associated with BMI showed that it was correlated with P1NP, follicle-stimulating hormone base, and luteinizing hormone peak in the overweight group and the obese group. Conclusions: Our findings showed that BMI was associated with P1NP, revealing the reduction of bone formation in overweight and obese girls with ICPP. During the diagnosis and treatment of girls with ICPP, attention should be paid to body weight and bone metabolism.


Asunto(s)
Pubertad Precoz , Femenino , Humanos , Índice de Masa Corporal , Pubertad Precoz/diagnóstico , Pubertad Precoz/metabolismo , Sobrepeso/complicaciones , Colágeno Tipo I/metabolismo , Osteocalcina , Hormona Luteinizante/metabolismo , Hormona Folículo Estimulante/metabolismo , Obesidad/complicaciones , Remodelación Ósea
5.
BMC Biol ; 20(1): 276, 2022 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-36482461

RESUMEN

BACKGROUND: Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization. RESULTS: We observed a unique IGF1+ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B+ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell-cell communication for decidualization was developed. An aberrant ratio conversion of IGF1+ stromal cells to IGF1R+ stromal cells is observed in unexplained RIF patients. CONCLUSIONS: Overall, a unique subpopulation of IGF1+ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases.


Asunto(s)
Placenta , Células del Estroma , Embarazo , Humanos , Femenino , Factor I del Crecimiento Similar a la Insulina/genética
6.
Plant Foods Hum Nutr ; 78(2): 320-328, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36947370

RESUMEN

Antioxidative and antiaging abilities of probiotic fermented ginseng (PG) were evaluated in Caenorhabditis elegans (C. elegans). Lifespan and effect on heat stress and acute oxidative stress in C. elegans were significantly enhanced by PG. Antioxidative enzymes such as T-SOD, GSH-PX, CAT were significantly up-regulated, and MDA, ROS and apoptosis levels were significantly down-regulated. At the same time, PG exerted antioxidant and anti-aging activities by reducing the expression of DAF-2 mRNA and increasing the expression of SKN-1 and SOD-3 mRNA in C. elegans. In addition, the mechanism of antioxidative and antiaging activities of PG was explored through gut microbiota sequencing and untargeted metabolomics. The results of gut microbiota indicated that PG could significantly improve the composition and structure of microbes in the gut of C. elegans, and the relative abundance of beneficial bacteria was up-regulated. Untargeted metabolomic results elucidated that PG modulated antioxidant and antiaging activities through neuroactive ligand-receptor interaction, Citrate cycle (TCA cycle), pyruvate metabolism, ascorbate and aldarate metabolism and D-Arginine and D-ornithine metabolism of C. elegans. These results indicated that PG had excellent antioxidant and anti-aging activities, providing research value for the development of functional foods and improvement of aging-related diseases.


Asunto(s)
Proteínas de Caenorhabditis elegans , Microbioma Gastrointestinal , Panax , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/farmacología , Envejecimiento , Estrés Oxidativo , Longevidad/fisiología , Superóxido Dismutasa/metabolismo , ARN Mensajero , Especies Reactivas de Oxígeno/metabolismo
7.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 54(2): 350-356, 2023 Mar.
Artículo en Zh | MEDLINE | ID: mdl-36949697

RESUMEN

Objective: To investigate the characteristic functional changes of the decidual natural killer (NK) cells and γδ T cells, two immunocytes in the decidua, at the maternal-fetal interface in in vitro fertilization-embryo transfer (IVF-ET) pregnancy. Methods: Decidual samples were collected from 12 women of natural pregnancy (NP) and 32 women of IVF-ET pregnancy, who were enrolled in the NP group and the IVF-ET group, respectively. Then part of the decidual samples were paraffin-embedded for HE staining and immunofluorescence staining, while the rest of the samples were digested and Percoll was used for isolating decidual immunocytes (DICs) by gradient centrifugation. Flow cytometry was used to determine the cell counts of decidual NK cells and γδ T cells and the expression levels of their surface activation markers, CD69 and NKG2D in the NP and the IVF-ET groups. In addition, the expression levels of IFN-γ, TNF-α, IL-17A, and IL-10, the intracellular cytokines, and granzyme B, perforin, and granulysin, the cytolytic granules, were measured. The characteristic changes in the relevant immunological indicators were compared and analyzed. Results: HE staining of the tissue specimens showed that the typical structure of decidua was observed, and that lymphocytes were enriched in the decidua. Immunofluorescence staining showed that the percentage of decidual NK (dNK) cells in nucleated cells of the IVF-ET group was significantly lower than that of the NP group ( P<0.05). Flow cytometry analysis of DICs showed that, compared with those of the NP group, the percentage of dNK cells of the IVF-ET group was decreased ( P<0.05) and the expression levels of IL-10 and perforin were significantly decreased in the IVF-ET group ( P<0.05). However, there was no significant difference in the decidual γδ T (dγδT) cell count between the two groups. The expression of IL-10, IL-17A, and perforin was downregulated in the IVF-ET group ( P<0.05). There was no significant difference in the expression of IFN-γ, TNF-α, granzyme B, and granulysin, the cellular function indicators ( P>0.05). Conclusion: The dNK cell count and the secretion of some intracellular cytokines of dNK and dγδT cells of women of IVF-ET pregnancy decreased to some degree, which suggests that certain changes may have taken place in the immunological microenvironment at the maternal-fetal interface. The specific effect of these changes on pregnancy outcomes needs further investigation.


Asunto(s)
Interleucina-10 , Interleucina-17 , Embarazo , Femenino , Humanos , Interleucina-10/metabolismo , Granzimas/metabolismo , Perforina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Decidua/metabolismo , Citocinas/metabolismo , Fertilización In Vitro
8.
Nanotechnology ; 33(47)2022 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-35981513

RESUMEN

Significant decoherence of the plasmon-emitter (i.e., plexcitonic) strong coupling systems hinders the progress towards their applications in quantum technology due to the unavoidable lossy nature of the plasmons. Inspired by the concept of spectral-hole-burning (SHB) for frequency-selective bleaching of the emitter ensemble, we propose 'cavity SHB' by introducing cavity modes with moderate quality factors to the plexcitonic system to boost its coherence. We show that the detuning of the introduced cavity mode with respect to the original plexcitonic system, which defines the location of the cavity SHB, is the most critical parameter. Simultaneously introducing two cavity modes of opposite detunings, the excited-state population of the emitter can be enhanced by 4.5 orders of magnitude within 300 fs, and the attenuation of the emitter's population can be slowed down by about 56 times. This theoretical proposal provides a new approach of cavity engineering to enhance the plasmon-emitter strong coupling systems' coherence, which is important for realistic hybrid-cavity design for applications in quantum technology.

9.
J Cell Mol Med ; 25(14): 6602-6617, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34075693

RESUMEN

N6-methyladenosine (m6A) is a well-known modification of RNA. However, as a key m6A methyltransferase, METTL16 has not been thoroughly studied in gastric cancer (GC). Here, the biological role of METTL16 in GC and its underlying mechanism was studied. Immunohistochemistry was used to detect the expression of METTL16 and relationship between METTL16 level and prognosis of GC was analysed. CCK8, colony formation assay, EdU assay and xenograft mouse model were used to study the effect of METTL16. Regulatory mechanism of METTL16 in the progression of GC was studied through flow cytometry analysis, RNA degradation assay, methyltransferase inhibition assay, RT-qPCR and Western blotting. METTL16 was highly expressed in GC cells and tissues and was associated with prognosis. In vitro and in vivo experiments confirmed that METTL16 promoted proliferation of GC cells and tumour growth. Furthermore, down-regulation of METTL16 inhibited proliferation by G1/S blocking. Significantly, we identified cyclin D1 as a downstream effector of METTL16. Knock-down METTL16 decreased the overall level of m6A and the stability of cyclin D1 mRNA in GC cells. Meanwhile, inhibition of methyltransferase activity reduced the level of cyclin D1. METTL16-mediated m6A methylation promotes proliferation of GC cells through enhancing cyclin D1 expression.


Asunto(s)
Proliferación Celular/genética , Ciclina D1/genética , Metiltransferasas/genética , Neoplasias Gástricas/genética , Adenosina/genética , Adulto , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Masculino , Metilación , Ratones , Persona de Mediana Edad , Pronóstico , Estabilidad del ARN/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología
10.
EMBO Rep ; 19(5)2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29491006

RESUMEN

Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid ß-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.


Asunto(s)
Acil-CoA Oxidasa/antagonistas & inhibidores , Acil-CoA Oxidasa/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Estrés Oxidativo , Sirtuinas/metabolismo , Acil-CoA Oxidasa/genética , Animales , Daño del ADN , Regulación hacia Abajo , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Peróxido de Hidrógeno , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Oxidación-Reducción , Peroxisomas/química , Pronóstico , Sirtuinas/genética
11.
Cell Mol Life Sci ; 76(11): 2111-2132, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30826860

RESUMEN

Although the pathogenesis of endometriosis is not fully understood, it is often considered to be an inflammatory disease. An increasing number of studies suggest that differential expression of anti-inflammatory cytokines (e.g., interleukin-4 and -10, and transforming growth factor-ß1) occurs in women with endometriosis, including in serum, peritoneal fluid and ectopic lesions. These anti-inflammatory cytokines also have indispensable roles in the progression of endometriosis, including by promoting survival, growth, invasion, differentiation, angiogenesis, and immune escape of the endometriotic lesions. In this review, we provide an overview of the expression, origin, function and regulation of anti-inflammatory cytokines in endometriosis, with brief discussion and perspectives on their future clinical implications in the diagnosis and therapy of the disease.


Asunto(s)
Endometriosis/inmunología , Endometrio/inmunología , Interleucina-10/inmunología , Interleucina-4/inmunología , Células del Estroma/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Progresión de la Enfermedad , Endometriosis/genética , Endometriosis/patología , Endometrio/patología , Células Epiteliales/inmunología , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-10/genética , Interleucina-4/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Macrófagos/inmunología , Macrófagos/patología , Transducción de Señal , Células del Estroma/patología , Linfocitos T/inmunología , Linfocitos T/patología , Factor de Crecimiento Transformador beta1/genética
12.
Oncologist ; 24(10): 1368-1374, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30872465

RESUMEN

BACKGROUND: The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. MATERIALS AND METHODS: Mutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed. RESULTS: Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. CONCLUSION: Operable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. IMPLICATIONS FOR PRACTICE: The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.


Asunto(s)
Adenocarcinoma/genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/genética , Adenocarcinoma/patología , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación
13.
Ann Surg Oncol ; 26(6): 1934-1941, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30820786

RESUMEN

BACKGROUND: The impact of specific co-mutations in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is unclear. METHODS: Tissues from 147 consecutive patients with resected EGFR-mutated lung adenocarcinomas treated at Sun Yat-Sen University Cancer Center were analyzed by next-generation sequencing (NGS). Associations between mutation status, patient baseline characteristics, and survival outcomes (disease-free survival [DFS] and overall survival [OS]) after surgical resection were analyzed. RESULTS: TP53 and protein kinase D (PKD) mutations were the two most frequently observed co-mutations in this cohort. Dual PKD/EGFR and TP53/EGFR mutations were found in 39 (27%) and 72 patients (49%), respectively, with dual TP53/EGFR mutations more commonly observed in male patients (P = 0.021). Both TP53 (hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.23-3.54, P = 0.007) and PKD co-mutations (HR 1.72, 95% CI 1.01-2.93, P = 0.044) were associated with shorter DFS, but not OS, in univariate analysis. In multivariate analysis, patients harboring PKD/TP53 co-mutations had shorter DFS compared with PKD-/TP53- cases (HR 2.49, 95% CI 1.15-5.37, P = 0.02). In a subgroup of never-smokers, TP53 co-mutations were associated with significantly worse OS (HR 50.11, 95% CI 2.39-1049.83, P = 0.012). CONCLUSION: TP53 and PKD mutations were the two most frequently observed co-mutations in resected EGFR-mutated lung adenocarcinoma. Both mutations were associated with poorer prognoses in affected patients.


Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Neoplasias Pulmonares/genética , Mutación , Proteína Quinasa C/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Receptores ErbB/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Neumonectomía , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
14.
Reproduction ; 157(3): 273-282, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30620718

RESUMEN

Decidualization renders the endometrium transiently receptive to an implanting blastocyst although the underlying mechanisms remain incompletely understood. The aim of this study was to determine the role of chemokine CXCL16 and its receptor CXCR6 in the decidualization during pregnancy. Here, the expression of CXCL16 was investigated in endometrial tissues, decidua and placenta in this study. Compared with endometrial tissue, protein expression of CXCL16 was significantly higher in tissues from the fertile control samples, especially in villus. Meanwhile, the primary trophoblast cells and decidual stromal cells (DSCs) secreted more CXCL16 and expressed higher CXCR6 compared to endometrial stromal cells (ESCs) in vitro. Stimulation with the inducer of decidualization (8-bromoadenosine 3',5'-cyclic with medroxyprogesterone acetate, 8-Br-cAMP plus MPA) significantly upregulated the expression of CXCL16 and CXCR6 in ESCs in vitro. After treatment with exogenous recombinant human CXCL16 (rhCXCL16) or trophoblast-secreted CXLC16, decidualised ESCs showed a significant decidual response, mainly characterised by increased prolactin (PRL) secretion. Simultaneously, PI3K/PDK1/AKT/Cyclin D1 pathway in decidualised ESCs were activated by rhCXCL16, and AKT inhibitor GS 690693 abolished the PRL secretion of ESCs that was triggered by rhCXCL16. Finally, the impaired CXCL16/CXCR6 expression could be observed at the maternal-foetal interface from patients who have experienced spontaneous abortion. This study suggests that the CXCL16/CXCR6 axis contributes to the progression of ESC decidualization by activating PI3K/PDK1/AKT/Cyclin D1 pathway. It unveils a new paradigm at the maternal-foetal interface in which CXCL16 is an initiator for the molecular crosstalk that enhances decidualization of ESCs.


Asunto(s)
Diferenciación Celular , Quimiocina CXCL16/metabolismo , Decidua/citología , Endometrio/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR6/metabolismo , Factores de Transcripción/metabolismo , Adulto , Células Cultivadas , Decidua/metabolismo , Endometrio/metabolismo , Femenino , Humanos , Fosforilación , Embarazo , Primer Trimestre del Embarazo , Células del Estroma/citología , Células del Estroma/metabolismo , Trofoblastos/citología , Trofoblastos/metabolismo
15.
Cell Commun Signal ; 17(1): 99, 2019 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-31429768

RESUMEN

BACKGROUND: Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS: Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS: Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS: CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.


Asunto(s)
Autofagia/efectos de los fármacos , Neoplasias Endometriales/tratamiento farmacológico , Estrógenos/farmacología , Glutamina/metabolismo , Proliferación Celular/efectos de los fármacos , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Glutaminasa/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas
16.
Clin Immunol ; 193: 60-69, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29410331

RESUMEN

Bladder cancer (BC) is a disease arising from the malignant cells of the urinary bladder. Myeloid-derived suppressor cells (MDSCs) expand broadly and have strong immunosuppressive activities in the cancer microenvironment. Determining how to inhibit the negative effects of MDSCs requires immediate attention. In this study, we found that granulocytic-MDSCs (G-MDSCs), which constitute one of the two types of MDSCs, were significantly increased in BC tissues compared with those in the adjacent bladder tissues. There was a robust negative correlation between the G-MDSCs and the CD8+ T cells in the BC tissues. In this study, we attempted to identify pharmacological approaches to eliminate MDSCs and restore T cell anti-tumor activities. It is necessary to explore a method to eliminate the detrimental effects of MDSCs. Cisplatin, a chemotherapy medication used to treat BC, not only rapidly kills proliferating cancer cells but also affects the tumor immune microenvironment. However, the mechanism underlying this phenomenon is largely unknown. In this study, we found that Cisplatin directly inhibited the proliferation and induced the apoptosis of T24 cells (a BC cell line), as well as decreased the percentage of the G-MDSCs in the population of peripheral blood mononuclear cells (PBMCs), which restored the expansion of the CD8+ T cells. In the C3H/He mouse BC model, Cisplatin treatment inhibited the progression of BC and effectively decreased the proportion of G-MDSCs. These results suggest that Cisplatin treatment enhances the anti-tumor function of CD8+ T cells by decreasing G-MDSCs. This finding provides a new perspective for Cisplatin treatment to prevent the progression of BC, particularly in patients with abnormally high levels of G-MDSCs.


Asunto(s)
Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Cisplatino/uso terapéutico , Granulocitos/fisiología , Células Supresoras de Origen Mieloide/fisiología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Antígeno CD11b/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Granulocitos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/efectos de los fármacos , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria/inmunología
17.
Reproduction ; 156(5): 397-404, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30087159

RESUMEN

It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK. Co-culture with endometrial stromal cells (nESCs) from healthy control or ectopic ESCs (eESCs) from women with EMS led to a significant increase in the IDO level in NK cells from peripheral blood, particularly eESCs, and an anti-TGF-ß neutralizing antibody suppressed these effects in vitro. NK cells co-cultured with ESC more preferentially inhibited the viability of nESCs than eESCs did, and pretreating with 1-methyl-tryptophan (1-MT), an IDO inhibitor, reversed the inhibitory effect of NK cells on eESC viability. These data suggest that ESCs induce IDO+NK cells differentiation partly by TGF-ß, and that IDO further restricts the cytotoxicity of NK cells in response to eESCs, which provides a potential therapeutic strategy for EMS patients, particularly those with a high number of impaired cytotoxic IDO+NK cells.


Asunto(s)
Endometriosis/inmunología , Endometrio/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Células Asesinas Naturales/enzimología , Adulto , Líquido Ascítico/inmunología , Estudios de Casos y Controles , Células Cultivadas , Endometrio/citología , Femenino , Humanos , Persona de Mediana Edad , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Células del Estroma/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven
18.
Hum Reprod ; 32(6): 1304-1317, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28383711

RESUMEN

STUDY QUESTION: Do regulatory T cells (Tregs) contribute to angiogenesis in endometriosis? SUMMARY ANSWER: High levels of CCL17 and CCL22 cause the recruitment of Tregs, upregulate the immunosuppression of Tregs and, in turn, may promote angiogenesis in endometrial cells in synergy with proinflammatory cytokines. WHAT IS ALREADY KNOWN: The peritoneal fluid of patients with endometriosis has a higher percentage of Tregs than that of normal individuals; however, the regulatory role of Tregs in the disease remains unclear. STUDY DESIGN, SIZE, DURATION: This study used primary human endometrial stromal cells (ESCs), monocytes (Mo), Tregs and human umbilical vein endothelial cells (HUVECs). All experiments were performed at least three times. PARTICIPANTS/MATERIALS, SETTING, METHODS: The migration of Tregs was evaluated by the transwell migration assay. The activation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase and p38 signaling pathways was examined using the In-Cell WesternTM (LI-COR®) western blot analysis system, as well as by traditional western blot analysis. Changes in the expression of CCL22, CCL17, transforming growth factor-beta 1 (TGF-ß1), Interleukin (IL)-1ß, tumor necrosis factor alpha (TNF-α), IL-8 and vascular endothelial growth factor (VEGF) in cell-culture supernatant were detected by ELISA. We analyzed the Tregs by multicolor flow cytometry to directly test the expression of CCR4, CD4, CD25, Foxp3, CTLA-4, CD39 and CD73. MAIN RESULTS AND THE ROLE OF CHANCE: Our results showed that ESCs-Mo co-culture produced significantly higher levels of CCL22 and CCL17 than ESCs or Mo cultured alone, and that estradiol (E2) or progesterone (P) further promoted this upregulation, demonstrating stronger chemotaxis on Tregs. The co-culture of ESCs with Mo stimulated TGF-ß1 secretion by Tregs, which could be inhibited by anti-CCL22 or/and anti-CCL17 neutralizing antibodies (Abs). The expression of CCR4 by Tregs was upregulated in ESCs-Mo co-culture, especially by treatment with E2 and/or P, and this effect could be abolished by anti-CCL22 and/or anti-CCL17-neutralizing Abs. The Treg-ESCs-Mo co-culture treated with E2 (10-8 mol/l) and P (10-8 mol/l) could enhance the immunosuppression of Tregs, as proved by the elevated expression of Foxp3, CTLA-4, CD39 and CD73 on Tregs. ESCs-Mo co-culture could significantly promote the secretion of IL-1ß and TNF-α. TGF-ß1 from Tregs could activate p38/ERK1/2 signaling pathways in ESCs, and IL-1ß and TNF-α produced by ESCs-Mo co-culture had synergistic roles with TGF-ß1. TGF-ß1 and the proinflammatory cytokines IL-1ß or TNF-α could synergistically promote IL-8 and VEGF expression in ESCs via the p38/ERK1/2 signaling pathways. The high levels of IL-8 and VEGF in the supernatant of ESCs stimulated the angiogenesis of HUVECs. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: This study was only performed in vitro using eutopic ESCs, instead of ectopic cells, from endometriosis patients. Therefore, it is necessary to do further experiments to determine whether Tregs promote angiogenesis in the endometriotic milieu in synergy with proinflammatory cytokines in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Co-targeting Tregs and proinflammatory cytokines may be an effective treatment for endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Ministry of Science and Technology of China 2015CB943300 to L.D.-J.; National Natural Science Foundation of China, item number 81200425 to  W.X.-Q.; National Natural Science Foundation of China, item number 81471548 to L.D.-J.; and The Research Fund for the Doctoral Program of Higher Education of China to W.X.-Q. (20110071120093). The authors have no conflicts of interest to declare.


Asunto(s)
Quimiocina CCL17/metabolismo , Quimiocina CCL22/metabolismo , Endometriosis/patología , Endometrio/patología , Endotelio Vascular/patología , Neovascularización Patológica/patología , Linfocitos T Reguladores/patología , Adulto , Biomarcadores/metabolismo , Comunicación Celular , Movimiento Celular , Células Cultivadas , Técnicas de Cocultivo , Endometriosis/inmunología , Endometriosis/metabolismo , Endometrio/irrigación sanguínea , Endometrio/inmunología , Endometrio/metabolismo , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Terapia de Inmunosupresión , Mediadores de Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Células del Estroma/inmunología , Células del Estroma/metabolismo , Células del Estroma/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
19.
Reproduction ; 154(6): 815-825, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28971893

RESUMEN

The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviors in vitro were analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1ß, IL-10 and transforming growth factor (TGF)-ß in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor ß neutralizing antibody (αhIL-10Rß) or αTGF-ß could partly reverse these effects of ESCs and macrophages on NK cells in vitro These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-ß, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.


Asunto(s)
Endometriosis/metabolismo , Endometrio/metabolismo , Interleucina-10/metabolismo , Células Asesinas Naturales/metabolismo , Macrófagos/metabolismo , Comunicación Paracrina , Células del Estroma/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Células Cultivadas , Microambiente Celular , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Endometriosis/inmunología , Endometriosis/patología , Endometrio/inmunología , Endometrio/patología , Femenino , Proteínas Ligadas a GPI/metabolismo , Humanos , Tolerancia Inmunológica , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Persona de Mediana Edad , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Perforina/metabolismo , Receptores de IgG/metabolismo , Transducción de Señal , Células del Estroma/inmunología , Células del Estroma/patología
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