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1.
Nat Immunol ; 24(8): 1358-1369, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37365386

RESUMEN

Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage-specific and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a bacterial lipopolysaccharide-induced extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in their capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.


Asunto(s)
Linfocitos B , Centro Germinal , Linfocitos T , Activación de Linfocitos , Comunicación Celular
2.
Nat Immunol ; 24(6): 1020-1035, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37127830

RESUMEN

While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.


Asunto(s)
Neoplasias , Linfocitos T Reguladores , Animales , Ratones , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Microambiente Tumoral , Neoplasias/metabolismo
3.
Nat Immunol ; 22(9): 1163-1174, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34426690

RESUMEN

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Factores de Transcripción Forkhead/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/genética , Diferenciación Celular/inmunología , Femenino , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/genética , Homeostasis/inmunología , Mediadores de Inflamación/metabolismo , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Síndrome de Respuesta Inflamatoria Sistémica/patología
4.
Immunity ; 55(7): 1173-1184.e7, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35700740

RESUMEN

Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4+ T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells suppress autoimmunity, pTreg cells enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms supporting their differentiation remain poorly understood. Here, we used genetic tracing to identify microbiota-induced pTreg cells and found that many of their distinguishing features were Foxp3 independent. Lineage-committed, microbiota-dependent pTreg-like cells persisted in the colon in the absence of Foxp3. While Foxp3 was critical for the suppression of a Th17 cell program, colitis, and mastocytosis, pTreg cells suppressed colonic effector T cell expansion in a Foxp3-independent manner. Thus, Foxp3 and the tolerogenic signals that precede and promote its expression independently confer distinct facets of pTreg functionality.


Asunto(s)
Factores de Transcripción Forkhead , Linfocitos T Reguladores , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica , Células Th17/metabolismo , Timocitos/metabolismo
5.
Immunity ; 54(5): 931-946.e11, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33838102

RESUMEN

Activation of the STAT5 transcription factor downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic effects of IL-2R signaling, it is unclear how STAT5 acts directly on the Foxp3 locus to promote its expression. Here, we report that IL-2 - STAT5 signaling converged on an enhancer (CNS0) during Foxp3 induction. CNS0 facilitated the IL-2 dependent CD25+Foxp3- precursor to Treg cell transition in the thymus. Its deficiency resulted in impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS0 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS0 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms minimizes autoimmunity.


Asunto(s)
Linaje de la Célula/inmunología , Factores de Transcripción Forkhead/inmunología , Tolerancia Inmunológica/inmunología , Interleucina-2/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Elementos de Facilitación Genéticos/inmunología , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Ratones , Receptores de Interleucina-2/inmunología , Factor de Transcripción STAT5/inmunología , Transducción de Señal/inmunología
6.
Immunity ; 53(5): 971-984.e5, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33176163

RESUMEN

Regulatory T (Treg) cell identity is defined by the lineage-specifying transcription factor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturally occurring genetic variation in wild-derived inbred mice, which enables the identification of DNA sequence motifs driving epigenetic features. Chromatin accessibility, TF binding, and gene expression patterns in resting and activated subsets of Treg cells, conventional CD4 T cells, and cells expressing a Foxp3 reporter null allele revealed that the majority of Foxp3-dependent changes occurred at sites not bound by Foxp3. Chromatin accessibility of these indirect Foxp3 targets depended on the presence of DNA binding motifs for other TFs, including TCF1. Foxp3 expression correlated with decreased TCF1 and reduced accessibility of TCF1-bound chromatin regions. Deleting one copy of the Tcf7 gene recapitulated Foxp3-dependent negative regulation of chromatin accessibility. Thus, Foxp3 defines Treg cell identity in a largely indirect manner by fine-tuning the activity of other major chromatin remodeling TFs such as TCF1.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Autoinmunidad/genética , Sitios de Unión , Ensamble y Desensamble de Cromatina , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Inmunohistoquímica , Masculino , Ratones , Motivos de Nucleótidos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Unión Proteica , Transactivadores/metabolismo
7.
Nature ; 610(7933): 752-760, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36070798

RESUMEN

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1-4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5-8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I-TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-ß-activating integrin αvß8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.


Asunto(s)
Células Presentadoras de Antígenos , Células Dendríticas , Células Epiteliales , Microbioma Gastrointestinal , Tolerancia Inmunológica , Linfocitos T Reguladores , Timo , Diferenciación Celular , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal/inmunología , Inmunidad Innata , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Timo/citología , Timo/inmunología , Factor de Crecimiento Transformador beta/inmunología , Células Presentadoras de Antígenos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Ganglios Linfáticos/inmunología
8.
Nature ; 572(7771): 665-669, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31435014

RESUMEN

Intestinal commensal bacteria can inhibit dense colonization of the gut by vancomycin-resistant Enterococcus faecium (VRE), a leading cause of hospital-acquired infections1,2. A four-strained consortium of commensal bacteria that contains Blautia producta BPSCSK can reverse antibiotic-induced susceptibility to VRE infection3. Here we show that BPSCSK reduces growth of VRE by secreting a lantibiotic that is similar to the nisin-A produced by Lactococcus lactis. Although the growth of VRE is inhibited by BPSCSK and L. lactis in vitro, only BPSCSK colonizes the colon and reduces VRE density in vivo. In comparison to nisin-A, the BPSCSK lantibiotic has reduced activity against intestinal commensal bacteria. In patients at high risk of VRE infection, high abundance of the lantibiotic gene is associated with reduced density of E. faecium. In germ-free mice transplanted with patient-derived faeces, resistance to VRE colonization correlates with abundance of the lantibiotic gene. Lantibiotic-producing commensal strains of the gastrointestinal tract reduce colonization by VRE and represent potential probiotic agents to re-establish resistance to VRE.


Asunto(s)
Bacteriocinas/metabolismo , Bacteriocinas/farmacología , Enterococcus faecium/efectos de los fármacos , Lactococcus lactis/metabolismo , Probióticos , Resistencia a la Vancomicina/efectos de los fármacos , Enterococos Resistentes a la Vancomicina/efectos de los fármacos , Animales , Antibacterianos/biosíntesis , Antibacterianos/aislamiento & purificación , Antibacterianos/metabolismo , Antibacterianos/farmacología , Bacteriocinas/genética , Bacteriocinas/aislamiento & purificación , Enterococcus faecium/crecimiento & desarrollo , Enterococcus faecium/aislamiento & purificación , Heces/microbiología , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/microbiología , Vida Libre de Gérmenes , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/crecimiento & desarrollo , Humanos , Lactococcus lactis/química , Lactococcus lactis/crecimiento & desarrollo , Lactococcus lactis/fisiología , Ratones , Pruebas de Sensibilidad Microbiana , Microbiota/genética , Nisina/química , Nisina/farmacología , Simbiosis/efectos de los fármacos , Vancomicina/farmacología , Enterococos Resistentes a la Vancomicina/crecimiento & desarrollo , Enterococos Resistentes a la Vancomicina/aislamiento & purificación
9.
Proc Natl Acad Sci U S A ; 119(43): e2208506119, 2022 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-36256824

RESUMEN

DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8+ T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8+ T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.


Asunto(s)
Neoplasias , Radioinmunoterapia , Ratones , Animales , Rayos X , Piroptosis , Inhibidores de Puntos de Control Inmunológico , Ligandos , Nucleotidiltransferasas/metabolismo
10.
Cancer Immunol Immunother ; 73(2): 36, 2024 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-38280003

RESUMEN

INTRODUCTION: Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. This study aimed to identify the biomarkers of clinical response and explore the immune response within the tumor microenvironment upon the AK104 therapy in advanced solid tumors. MATERIAL AND METHODS: Gene expression profiles of paired pre- and post-treatment tumor tissues from twenty-one patients were analyzed. The association of gene expression levels with either clinical efficacy or prognosis was evaluated and subsequently validated with published datasets using log-rank for Kaplan-Meier estimates. Comparative immune profile analyses of tumor microenvironment before and after AK104 treatment were conducted. The visualization of tumor-infiltrating lymphocytes was performed using multiplex immunohistochemistry. The predictive value of CD74 was further validated with protein expression by immunohistochemistry. RESULTS: Baseline CD74 gene expression was associated with favorable patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11-1.03, p = 0.0463), which was further confirmed with the published datasets. Tumors with high CD74 gene expression at baseline were more likely to exhibit an immune-inflamed microenvironment. AK104 efficiently enhanced the infiltration of immune cells in the tumor microenvironment. Additionally, high CD74 protein expression (≥ 10% of the tumor area occupied by CD74 stained immune cells) at baseline was associated with better progressive-free survival (HR = 0.21, 95% CI 0.06-0.68, p = 0.0065) and OS (HR = 0.35, 95% CI 0.12-1.08, p = 0.0615). CONCLUSIONS: Our findings demonstrate that CD74 is a promising predictive biomarker for AK104 therapeutic response in advanced solid tumors. Trial registration number NCT03261011.


Asunto(s)
Neoplasias , Receptor de Muerte Celular Programada 1 , Humanos , Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4/metabolismo , Linfocitos Infiltrantes de Tumor , Neoplasias/tratamiento farmacológico , Microambiente Tumoral
11.
Small ; 20(3): e2305181, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37699749

RESUMEN

As a steady stream of electronic devices being discarded, a vast amount of electronic substrate waste of petroleum-based nondegradable polymers is generated, raising endless concerns about resource depletion and environmental pollution. With coupled reagent (CR)-grafted artificial marble waste (AMW@CR) as functional fillers, polylactic acid (PLA)-based highly stretchable biodegradable green composite (AMW@CR-SBGC) is prepared, with elongation at break up to more than 250%. The degradation mechanism of AMW@CR-SBGC is deeply revealed. AMW@CR not only contributed to the photodegradation of AMW@CR-SBGC but also significantly promoted the water degradation of AMW@CR-SBGC. More importantly, AMW@CR-SBGC showed great potential as sustainable green electronic substrates and AMW@CR-SBGC-based electronic skin can simulate the perception of human skin to strain signals. The outstanding programmable degradability, recyclability, and reusability of AMW@CR-SBGC enabled its application in transient electronics. As the first demonstration of artificial marble waste in electronic substrates, AMW@CR-SBGC killed three birds with one stone in terms of waste resourcing, e-waste reduction, and saving nonrenewable petroleum resources, opening up vast new opportunities for green electronics applications in areas such as health monitoring, artificial intelligence, and security.

12.
Small ; 20(1): e2304541, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37661573

RESUMEN

The current development of single electrocatalyst with multifunctional applications in overall water splitting (OWS) and zinc-air batteries (ZABs) is crucial for sustainable energy conversion and storage systems. However, exploring new and efficient low-cost trifunctional electrocatalysts is still a significant challenge. Herein, the antiperovskite CuNCo3 prototype, that is proved to be highly efficient in oxygen evolution reaction but severe hydrogen evolution reaction (HER) performance, is endowed with optimum HER catalytic properties by in situ-derived interfacial engineering via incorporation of molybdenum (Mo). The as-prepared Mo-CuNCo3 @CoN nanowires achieve a low HER overpotential of 58 mV@10 mA cm-2 , which is significantly higher than the pristine CuNCo3 . The assembled CuNCo3 -antiperovskite-based OWS not only entails a low overall voltage of 1.56 V@10 mA cm-2 , comparable to most recently reported metal-nitride-based OWS, but also exhibits excellent ZAB cyclic stability up to 310 h, specific capacity of 819.2 mAh g-1 , and maximum power density of 102 mW cm-2 . The as-designed antiperovskite-based ZAB could self-power the OWS system generating a high hydrogen rate, and creating opportunity for developing integrated portable multifunctional energy devices.

13.
Chem Res Toxicol ; 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39078936

RESUMEN

The outbreak of e-cigarette or vaping use-associated lung injury (EVALI) in the United States in 2019 led to a total of 2807 hospitalizations with 68 deaths. While the exact causes of this vaping-related lung illness are still being debated, laboratory analyses of products from victims of EVALI have shown that vitamin E acetate (VEA), an additive in some tetrahydrocannabinol (THC)-containing products, is strongly linked to the EVALI outbreak. Because of its similar appearance and viscosity to pure THC oil, VEA was used as a diluent agent in cannabis oils in illicit markets. A potential mechanism for EVALI may involve VEA's thermal decomposition product, ketene, a highly poisonous gas, being generated under vaping conditions. In this study, a novel approach was developed to evaluate ketene production from VEA vaping under measurable temperature conditions in real-world devices. Ketene in generated aerosols was captured by two different chemical agents and analyzed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method takes advantage of the high sensitivity and specificity of tandem mass spectrometry and appears to be more suitable than GC-MS for the analysis of large batches of samples. Our results confirmed the formation of ketene when VEA was vaped. The production of ketene increased with repeat puffs and showed a correlation to temperatures (200 to 500 °C) measured within vaping devices. Device battery power strength, which affects the heating temperature, plays an important role in ketene formation. In addition to ketene, the organic oxidant duroquinone was also obtained as another thermal degradation product of VEA. Ketene was not detected when vitamin E was vaped under the same conditions, confirming the importance of the acetate group for its generation.

14.
BJOG ; 131(7): 952-960, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38168494

RESUMEN

OBJECTIVE: To assess pelvic floor muscle (PFM) strength and influencing factors among healthy women at different life stages. DESIGN: Multicentre cross-sectional study. SETTING: Fourteen hospitals in China. POPULATION: A total of 5040 healthy women allocated to the following groups (with 1680 women per group): premenopausal nulliparous, premenopausal parous and postmenopausal. METHODS: The PFM strength was evaluated by vaginal manometry. Multivariate logistic regression was used to determine the influencing factors for low PFM strength. MAIN OUTCOME MEASURES: Maximum voluntary contraction pressure (MVCP). RESULTS: The median MVCP values were 36, 35 and 35 cmH2O in premenopausal nulliparous (aged 19-51 years), premenopausal parous (aged 22-61 years), and postmenopausal (aged 40-86 years) women, respectively. In the premenopausal nulliparous group, physical work (odds ratio, OR 2.05) was the risk factor for low PFM strength, which may be related to the chronic increased abdominal pressure caused by physical work. In the premenopausal parous group, the number of vaginal deliveries (OR 1.28) and diabetes (OR 2.70) were risk factors for low PFM strength, whereas sexual intercourse (<2 times per week vs. none, OR 0.55; ≥2 times per week vs. none, OR 0.56) and PFM exercise (OR 0.50) may have protective effects. In the postmenopausal group, the number of vaginal deliveries (OR 1.32) and family history of pelvic organ prolapse (POP) (OR 1.83) were risk factors for low PFM strength. CONCLUSIONS: Physical work, vaginal delivery, diabetes and a family history of POP are all risk factors for low PFM strength, whereas PFM exercises and sexual life can have a protective effect. The importance of these factors varies at different stages of a woman's life.


Asunto(s)
Manometría , Fuerza Muscular , Diafragma Pélvico , Posmenopausia , Premenopausia , Vagina , Humanos , Femenino , Persona de Mediana Edad , Estudios Transversales , Diafragma Pélvico/fisiología , Adulto , Manometría/métodos , Fuerza Muscular/fisiología , Anciano , Posmenopausia/fisiología , Premenopausia/fisiología , Vagina/fisiología , Factores de Riesgo , Anciano de 80 o más Años , Adulto Joven , Paridad , China/epidemiología , Contracción Muscular/fisiología , Embarazo
15.
BMC Cardiovasc Disord ; 24(1): 300, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38867152

RESUMEN

BACKGROUND: Diabetes is a common chronic metabolic disease. The progression of the disease promotes vascular inflammation and the formation of atherosclerosis, leading to cardiovascular disease. The coronary artery perivascular adipose tissue attenuation index based on CCTA is a new noninvasive imaging biomarker that reflects the spatial changes in perivascular adipose tissue attenuation in CCTA images and the inflammation around the coronary arteries. In this study, a radiomics approach is proposed to extract a large number of image features from CCTA in a high-throughput manner and combined with clinical diagnostic data to explore the predictive ability of vascular perivascular adipose imaging data based on CCTA for coronary heart disease in diabetic patients. METHODS: R language was used for statistical analysis to screen the variables with significant differences. A presegmentation model was used for CCTA vessel segmentation, and the pericoronary adipose region was screened out. PyRadiomics was used to calculate the radiomics features of pericoronary adipose tissue, and SVM, DT and RF were used to model and analyze the clinical data and radiomics data. Model performance was evaluated using indicators such as PPV, FPR, AAC, and ROC. RESULTS: The results indicate that there are significant differences in age, blood pressure, and some biochemical indicators between diabetes patients with and without coronary heart disease. Among 1037 calculated radiomic parameters, 18.3% showed significant differences in imaging omics features. Three modeling methods were used to analyze different combinations of clinical information, internal vascular radiomics information and pericoronary vascular fat radiomics information. The results showed that the dataset of full data had the highest ACC values under different machine learning models. The support vector machine method showed the best specificity, sensitivity, and accuracy for this dataset. CONCLUSIONS: In this study, the clinical data and pericoronary radiomics data of CCTA were fused to predict the occurrence of coronary heart disease in diabetic patients. This provides information for the early detection of coronary heart disease in patients with diabetes and allows for timely intervention and treatment.


Asunto(s)
Tejido Adiposo , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Vasos Coronarios , Diabetes Mellitus Tipo 2 , Valor Predictivo de las Pruebas , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Persona de Mediana Edad , Tejido Adiposo/diagnóstico por imagen , Masculino , Femenino , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Anciano , Vasos Coronarios/diagnóstico por imagen , Interpretación de Imagen Radiográfica Asistida por Computador , Máquina de Vectores de Soporte , Adiposidad , Pronóstico , Tejido Adiposo Epicárdico , Radiómica
16.
Environ Res ; 249: 118452, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38360169

RESUMEN

In this study, multilayer self-assembled multifunctional bamboo shoot shell biochar microspheres (BSSBM) were prepared, in which bamboo shoot shell biochar was used as the carrier, titanium dioxide as the intermediate medium, and chitosan as the adhesion layer. The adsorption behavior of BSSBM on heavy metals Ag(I) and Pd(II), antibiotics, and dye wastewater was systematically analyzed. BSSBM shows a wide range of adsorption capacity. BSSBM is a promising candidate for the purification of real polluted water, not only for metal ions, but also for Tetracycline (TC) and Methylene Blue (MB). The maximum adsorption amounts of BSSBM on Pd(II), Ag(I), TC and MB were 417.3 mg/g, 222.5 mg/g, 97.2 mg/g and 42.9 mg/g, respectively.The adsorption of BSSBM on Pd(II), MB and TC conformed to the quasi-first kinetic model, and the adsorption on Ag(I) conformed to the quasi-second kinetic model. BSSBM showed remarkable selective adsorption capacity for Ag(I) and Pd(II) in a multi-ion coexistence system. BSSBM not only realized the high value-added utilization of waste, but also had the advantages of low cost, renewable and selective adsorption. BSSBM demonstrated its potential as a new generation of multifunctional adsorbent, contributing to the recovery of rare/precious metals and the treatment of multi-polluted water.


Asunto(s)
Microesferas , Contaminantes Químicos del Agua , Purificación del Agua , Adsorción , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/análisis , Purificación del Agua/métodos , Carbón Orgánico/química , Metales Pesados/química , Metales Pesados/análisis , Brotes de la Planta/química , Cinética , Quitosano/química , Bambusa/química , Aguas Residuales/química , Antibacterianos/química
17.
Mikrochim Acta ; 191(5): 262, 2024 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-38613581

RESUMEN

Rapid and sensitive detection of carcinoembryonic antigen (CEA) is of great significance for cancer patients. Here, molybdenum (Mo) was doped into bismuth oxide (Bi2O3) by one-pot hydrothermal method forming porous tremella Bi2MoO6 nanocomposites with a larger specific surface area than the spherical structure. Then, a new kind of hydrangea-like TiO2/Bi2MoO6 porous nanoflowers (NFs) was prepared by doping titanium into Bi2MoO6, where titanium dioxide (TiO2) grew in situ on the surface of Bi2MoO6 nanoparticles (NPs). The hydrangea-like structure provides larger specific surface area, higher electron transfer ability and biocompatibility as well as more active sites conducive to the attachment of anti-carcinoembryonic antigen (anti-CEA) to TiO2/Bi2MoO6 NFs. A novel label-free electrochemical immunosensor was then constructed for the quantitative detection of CEA using TiO2/Bi2MoO6 NFs as sensing platform, showing a good linear relationship with CEA in the concentration range 1.0 pg/mL ~ 1.0 mg/mL and a detection limit of 0.125 pg/mL (S/N = 3). The results achieved with the designed immunosensor are comparable with many existing immunosensors used for the detection of CEA in real samples.


Asunto(s)
Técnicas Biosensibles , Bismuto , Hydrangea , Molibdeno , Humanos , Biomarcadores de Tumor , Antígeno Carcinoembrionario , Porosidad , Inmunoensayo
18.
Lancet Oncol ; 24(10): 1134-1146, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37797632

RESUMEN

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma Hepatocelular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Hepáticas , Neoplasias del Cuello Uterino , Humanos , Masculino , Femenino , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Empatía , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
19.
Opt Lett ; 48(17): 4605-4608, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37656566

RESUMEN

Due to its powerful penetration, and greater spatial resolution than microwaves and ultrasonic waves, the terahertz technique stands out as being particularly useful in identifying thin glue layers in multilayered materials. However, the arrival times of echoes are challenging to pinpoint from the experimental data because of the temporal form of the incident pulse and the system noise. Here, two terahertz signal sparse deconvolution algorithms are studied to more accurately identify the times of the echoes. Using the circulant structure of the convolution matrix, the method's computation time can be lowered to hundreds of milliseconds. In addition, a method based on group velocity dispersion is investigated to reduce the impact of time-varying pulses with minimal computational expense. The presented algorithms have the potential to be employed in real-time inspection in production lines due to their quick speed and high confidence.

20.
Eur Radiol ; 33(3): 1779-1791, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36149482

RESUMEN

OBJECTIVES: To explore the risk factors for recurrence of arterial complications after pancreatectomy during the period of covered stent implantation and to provide some opinions on peri-stent implantation management. METHODS: Data on patients implanted with covered stents due to arterial complications after pancreatectomy between January 2017 and December 2021 were analyzed retrospectively. Technical success, clinical success, recurrence, and survival were evaluated to elucidate the practicability of covered stents. Wilson score, Random Forest, logistic regression, and Pearson's chi-square test with bootstrap aggregation were performed for determining the perioperative risk factors for recurrence. RESULTS: Among all fifty-five patients, success stent implantation (technical success) was achieved 100%. Patients who were hemodynamically stabilized without further treatment for artery complications in situ (clinical success) accounted for 89.1%. Based on statistical analysis, pre-stent implantation pancreatic fistula was identified as a robust recurrence-related risk factor for preoperative assessment (p = 0.02, OR = 4.5, 95% CI [1.2, 16.9]; pbootstrap = 0.02). Post-stent implantation pancreatic fistula (p = 0.01, OR 4.5, 95% CI [1.4, 14.6]; pbootstrap < 0.05) and SMA branches or GDA stumps (p = 0.02, OR 3.4, 95% CI [1.1, 10.3]) were relevant to recurrence. The survival rate during hospitalization was 87.3%. All survivors were free from recurrence during the subsequent follow-up. Vasospasm and stent occlusion were observed as short-term and long-term complications, respectively. CONCLUSION: A covered stent implantation is a feasible and effective treatment option for post-pancreatectomy arterial complications. Rigorous management of pancreatic fistula, timely detection of problems, sensible strategies during stent implantation, and reasonable anticoagulation therapy are necessary for a better prognosis. KEY POINTS: • A covered stent is feasible for various artery-related complications after pancreatectomy and has an ideal therapeutic effect. • Pancreatic fistula during the perioperative period of the covered stent is an independent risk factor for recurrent arterial complications and SMA branches or GDA stumps are prone to be recurrent offending arteries. • Rigorous management of pancreatic fistula, timely detection of problems, sensible strategies during stent implantation, and reasonable anticoagulation therapy are necessary for a better prognosis.


Asunto(s)
Fístula Pancreática , Stents , Humanos , Estudios Retrospectivos , Arterias , Resultado del Tratamiento , Medición de Riesgo , Anticoagulantes
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