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Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.
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BACKGROUND: Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. METHODS: We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. RESULTS: Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. CONCLUSIONS: HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Antígenos HLA-A , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/genética , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Antígenos HLA-A/inmunología , Antígenos HLA-A/genética , Femenino , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/metabolismoRESUMEN
Reprograming of chromatin structures and changes in gene expression are critical for plant male gamete development, and epigenetic marks play an important role in these processes. Histone variant H3.3 is abundant in euchromatin and is largely associated with transcriptional activation. The precise function of H3.3 in gamete development remains unclear in plants. Here, we report that H3.3 is abundantly expressed in Arabidopsis anthers and its knockout mutant h3.3-1 is sterile due to male sterility. Transcriptome analysis of young inflorescence has identified 2348 genes downregulated in h3.3-1 mutant, among which 1087 target genes are directly bound by H3.3, especially at their 3' ends. As a group, this set of H3.3 targets is enriched in the reproduction-associated processes including male gamete generation, pollen sperm cell differentiation and pollen tube growth. The function of H3.3 in male gamete development is dependent on the Anti-Silencing Factor 1A/1B (ASF1A/1B)-Histone regulator A (HIRA)-mediated pathway. Our results suggest that ASF1A/1B-HIRA-mediated H3.3 deposition at its direct targets for transcription activation forms the regulatory networks responsible for male gamete development.
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Arabidopsis , Histonas , Histonas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Semillas/metabolismo , Fertilidad , Células Germinativas/metabolismo , Cromatina/metabolismoRESUMEN
OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.
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Autoanticuerpos , Biomarcadores , Proteína-Arginina N-Metiltransferasas , Esclerodermia Sistémica , Esclerodermia Sistémica/inmunología , Humanos , Biomarcadores/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Proteína-Arginina N-Metiltransferasas/inmunología , Animales , Ratones , Femenino , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , Lupus Eritematoso Sistémico/inmunología , Inmunoprecipitación/métodos , Proteómica/métodosRESUMEN
Sulfur-driven autotrophic denitrification (S0dAD) was employed to remove residual nitrogen from the biological effluent of landfill leachate after partial nitrification and denitrification pretreatment. The performance of S0dAD were assessed with various NOx--N (NO2--N and NO3--N) loadings over a 185-day operational period. The results demonstrated that a notable NOx--N removal efficiency of 97.8 ± 2.0% was achieved under nitrogen removal rates of 0.12 ± 0.02 kg N/(m3· d), leading to total nitrogen concentrations of 8.6 ± 3.8 mg/L in the effluent. Batch experiments revealed competitive utilization of nitrogenous electron acceptors, with NO2--N demonstrating 2-4 times higher denitrification rates than NO3--N under coexistence conditions. Genus-level microbial community identified that Thiobacillus and Sulfurovum was highly enriched with as key denitrifying bacteria in the S0dAD system. These findings provide insights for advanced nitrogen removal coupling S0dAD with partial nitrification and denitrification process for landfill leachate treatment.
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Desnitrificación , Nitrificación , Nitrógeno , Azufre , Contaminantes Químicos del Agua , Nitrógeno/metabolismo , Azufre/metabolismo , Contaminantes Químicos del Agua/metabolismo , Procesos AutotróficosRESUMEN
BACKGROUND: Traditional radiotherapy and chemotherapy have been intensively studied for their role in the treatment of tumours. However, these therapies often cause side effects for patients, which calls for the development of novel treatment options for tumours. B-cell lymphoma-2 (Bcl-2)/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) reportedly apoptosis-inducing effects in tumour cells and is associated with the progression and treatment of multiple tumours. Nevertheless, little is known about its potential role in tumour diagnosis and targeted therapy. FINDINGS: The results of the study demonstrated that the interaction of BNIP3 with HDAC1 may affect the progression of breast invasive cancer (BRCA), sarcoma (SARC), kidney renal clear cell carcinoma (KIRC), and low-grade glioma (LGG). BNIP3 seemed to exert its effects in BRCA and SARC primarily through gene silencing and integrator complex, and in KIRC and LGG, mainly by affecting olfactory function, suggesting that targeted therapy can be developed based on the above signalling pathway and downstream molecules. INTERPRETATION: BNIP3 has emerged as a promising therapeutic and diagnostic target for BRCA, SARC, KIRC, and LGG, providing new insights into tumour molecular therapies in the clinic.
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Neoplasias de la Mama , Carcinoma de Células Renales , Glioma , Neoplasias Renales , Sarcoma , Humanos , Femenino , Pronóstico , Biomarcadores , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Extreme environmental changes threaten plant survival and worldwide food production. In response to osmotic stress, the plant hormone abscisic acid (ABA) activates stress responses and restricts plant growth. However, the epigenetic regulation of ABA signaling and crosstalk between ABA and auxin are not well known. Here, we report that the histone variant H2A.Z-knockdown mutant in Arabidopsis Col-0, h2a.z-kd, has altered ABA signaling and stress responses. RNA-sequencing data showed that a majority of stress-related genes are activated in h2a.z-kd. In addition, we found that ABA directly promotes the deposition of H2A.Z on SMALL AUXIN UP RNAs (SAURs), and that this is involved in ABA-repression of SAUR expression. Moreover, we found that ABA represses the transcription of H2A.Z genes through suppressing the ARF7/19-HB22/25 module. Our results shed light on a dynamic and reciprocal regulation hub through H2A.Z deposition on SAURs and ARF7/19-HB22/25-mediated H2A.Z transcription to integrate ABA/auxin signaling and regulate stress responses in Arabidopsis.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Ácido Abscísico/metabolismo , Ácidos Indolacéticos/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Histonas/metabolismo , Epigénesis Genética , ARN/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
OBJECTIVES: Systemic sclerosis (SSc) is a rare rheumatic disease characterized by vascular damage, dysregulated immune response, and fibrosis. Interleukin-11 (IL-11) is upregulated in SSc. This study aimed to investigate the pathological and therapeutic role of the IL-11 trans-signaling pathway in SSc. METHODS: Plasma IL-11 level was evaluated in 32 patients with SSc and 15 healthy controls, while the expression levels of ADAM10, ADAM17, IL-11, IL-11 Rα, or IL-11 co-stained with CD3 or CD163 in the skin of SSc patients and healthy controls were analyzed. Fibroblasts were treated with IL-11 and ionomycin to evaluate the profibrotic effect of IL-11 trans-signaling pathway. TJ301 (sgp130Fc) and WP1066 (a JAK2/STAT3 inhibitor) intervention groups were set up to investigate the antifibrotic effect of targeting IL-11. RESULTS: Levels of plasma IL-11 were extremely low in most SSc patients and healthy controls. In contrast, levels of IL-11, IL-11 Rα, and ADAM10, but not ADAM17, were significantly elevated in the skin of SSc patients. Moreover, the numbers of IL-11+ CD3+ cells and IL-11+ CD163+ cells were increased in the skin of SSc patients. Besides, IL-11 and ADAM10 were also elevated in the skin and pulmonary of bleomycin-induced SSc mouse. Fibroblasts co-stimulated with IL-11 and ionomycin showed increased expression of COL3 and phosphorylation of STAT3, which could be inhibited by TJ301 or WP1066. TJ301 also ameliorated skin and lung fibrosis in BLM-induced SSc mouse. CONCLUSIONS: IL-11 induces fibrosis in SSc by regulating the trans-signaling pathway. Blockage of sgp130Fc or inhibition of the JAK2/STAT3 pathway could ameliorate the profibrotic effect of IL-11.
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Interleucina-11 , Esclerodermia Sistémica , Humanos , Animales , Ratones , Interleucina-11/efectos adversos , Interleucina-11/metabolismo , Ionomicina/efectos adversos , Ionomicina/metabolismo , Fibrosis , Esclerodermia Sistémica/tratamiento farmacológico , Piel/patología , Transducción de Señal , Fibroblastos/patología , Janus Quinasa 2/efectos adversos , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
The objective of the study was to explore the impact of paternal age on the risk of congenital anomalies and birth outcomes in infants born in the USA between 2016 and 2021. This retrospective cohort study used data from the National Vital Statistics System (NVSS) database, a data set containing information on live birth in the USA between 2016 and 2021. Newborns were divided into four groups based on their paternal age (< 25, 25-34, 35-44, and > 44 years) and using the 25-34 age group as a reference. The primary outcomes were congenital anomalies involving structural anomalies and chromosome anomalies. Secondary outcomes were preterm birth, low birth weight, severe neonatal perinatal asphyxia, and admission to neonatal intensive care units (NICU). A multivariable logistic regression model was used to analyze the association between paternal age and outcomes. Overall, 17,764,695 live births were included in the final analyses. After adjusting confounding factors, advanced paternal age > 44 years was associated with increased odds of congenital anomalies (adjusted odds ratio (aOR) = 1.17, 95%CI 1.12-1.21) compared with the 25-34 age group, mainly for the chromosomal anomalies (aOR = 1.59, 95%CI 1.40-1.78) but not the structure anomalies (aOR = 1.03, 95%CI 0.97-1.09). The risk of preterm delivery, low birth weight, and NICU hospitalization in their infants was increased by advanced parental age as well. Conclusion: Advanced paternal age increases the risk of congenital anomalies, especially chromosomal anomalies in their offspring, implying prenatal genetic counseling is required. What is Known: ⢠There's a rising trend of advanced paternal age, which is associated with an increased likelihood of premature birth and low birth weight in their offspring. However, the exploration between paternal age and congenital abnormalities in offspring was limited and contradictory. What is New: ⢠Infants with a paternal age > 44 years were more likely to be born with congenital anomalies, especially chromosomal anomalies.
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Anomalías Congénitas , Edad Paterna , Nacimiento Prematuro , Adulto , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Estudios de Cohortes , Anomalías Congénitas/epidemiología , Anomalías Congénitas/etiología , Recién Nacido de Bajo Peso , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , MasculinoRESUMEN
Macrophage polarization mediates the development of inflammatory diseases. However, the polarization status at various stages of gout is not fully understood. Our study aimed to define the evolution of macrophage polarization in acute and chronic gout. Normal human synovium and synovium with tophi were collected for immunofluorescence (IF). Rat gouty joints were collected for joint thickness assessment and pathological evaluation. Tissue mRNA expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were evaluated. Mouse peritoneal macrophages and THP-1 derived macrophages were stimulated by monosodium urate (MSU) crystals and were collected for detection of interleukin (IL) -1ß and IL-37 levels and iNOS/Arg-1 ratio. Arg-1 and IL-37 were highly expressed in normal synovium and synovium with tophi. In rat gouty joints, the inflammatory cell counts and ankle thickness began to increase at 2 h, peaked at 24 h, and was decreased spontaneously. An increase in macrophages preceded the neutrophils infiltration. Infiltration of M1 was positively related with the severity of arthritis. M2 appeared in an early stage (at 2 h) of inflammation. The number of M1 macrophages was comparable to that of M2 from 2 to 12 h and exceeded M2 number at 18 h and 24 h. The ratios of M2/M1 reversed at 48 h and remained reversed until 120 h. In mice gouty joints, iNOS/Arg-1 mRNA ratio was significantly higher than the that in control group at 8 h. The proportion of neutrophils and M1-macrophages reached peak at 4 h in mice model with peritoneal gout. Concentration of IL-1ß and ratio of iNOS/Arg-1 were increased at 6 h, peaked at 48 h, and were then decreased at 72 h in vitro, while the concentration of IL-37 peaked at 2 h and then decreased. In summary, altered macrophage polarization was observed in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at early stage and into M2 at later stage while the macrophages in chronic gout mainly were only polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.
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Arginasa , Gota , Animales , Gota/metabolismo , Humanos , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , ARN Mensajero/metabolismo , Ácido Úrico/metabolismoRESUMEN
New mononuclear and dinuclear Ru(II) coordination compounds with the 2,7-bisbenzoimidazolyl-naphthyridine ligand have been synthesized and characterized by UV-vis, NMR, and MALDI-TOF. The molecular structures for Ru(II) compounds were determined by single-crystal X-ray diffraction. With the expansion of ligand π-conjugation and the increase in the complexed Ru number, the maximum emission wavelength red-shifted from 696 to 786 nm. The binding mode between complexes and DNA was predicted by molecular docking, which is intercalations and π-π stacking interactions with the surrounding bases. The intercalation mode of DNA binding was then determined by DNA titration and ethidium bromide (EB) displacement experiments. The antigrowth effects of complexes RuY, RuY1, and RuY2 were tested in HaCat (normal cells), HeLa (cervical cancer), A549 (lung cancer), and A549/DDP (cisplatin-resistant lung cancer) through the MTT assay. The dinuclear complex RuY2 was superior to mononuclear complexes and cisplatin in the cisplatin-resistant cell line. Confocal imaging proved that the subcellular localization of Ru(II) complexes was mitochondria; moreover, apoptosis was detected by flow cytometry. All three complexes showed a dose-dependent manner in all four cell lines. All Ru(II) complexes were found to have reactive oxygen species (ROS). The finding indicated that these Ru(II) complexes caused cell death by both DNA disruption and ROS. This study helps to explore the potential of the polynuclear Ru(II) complexes for the combination of NIR imaging and Pt-resistant cancer therapy.
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Antineoplásicos , Complejos de Coordinación , Neoplasias Pulmonares , Rutenio , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , ADN/química , Humanos , Ligandos , Mitocondrias , Simulación del Acoplamiento Molecular , Platino (Metal)/farmacología , Especies Reactivas de Oxígeno/metabolismo , Rutenio/química , Rutenio/farmacologíaRESUMEN
Cisplatin (CDDP) is the first generation of platinum-based drug and is widely used to treat many cancers due to its potency. The present study aims to explore the effects of CDDP on lung carcinoma and its relationship with macrophage phagocytosis. In in vitro study, murine and human lung cancer cell lines were applied and treated with CDDP, CD47 antibody (aCD47), or CDDP plus aCD47. In in vivo study, a tumor xenograft animal model was treated with CDDP, aCD47, or CDDP plus aCD47. Real-time PCR was applied to determine the mRNA expressions. Enzyme-linked immunosorbent assay (ELISA), Western blotting, and Immunofluorescent staining were applied to determine the protein expressions. Flow cytometry was applied to analyze cell apoptosis, phagocytosis, and specific cell populations. CDDP enhanced the expressions of CD47 in lung cancer cells. Interestingly, the blockage of CD47 enhanced the macrophages' phagocytic activity on the CDDP-treated tumor cells. The treatment of CDDP and aCD47 exhibited anti-tumor effects and prolonged the LLC tumor-bearing mice survival time. Mechanistic studies revealed that the treatment of CDDP and aCD47 regulated the phagocytic activity of macrophage, percentage of CD8+ T cells, and cytokines (tumor growth factor (TGF)-ß, interleukin (IL)12p70, and interferon (IFN)-γ) in the tumor-bearing model. CD47 blockade enhanced therapeutic efficacy of cisplatin against lung carcinoma in vivo and in vitro.
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Antígeno CD47/antagonistas & inhibidores , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Neoplasias Pulmonares/patología , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacosRESUMEN
Asthma is an allergic inflammatory lung disease affecting nearly 300 million people worldwide. To better understand asthma, new regulators must be identified. We conducted a study to investigate the effect and mechanisms of action of surfactant protein A (SPA) in OVA-induced asthmatic mice. Treatment with SPA delayed the onset of asthma, decreased its severity, as well as notably suppressed pro-inflammatory cytokine production. Furthermore, SPA-treated mice possessed more leukocytes; more CD4+ T cells infiltrated the spleen in the SPA-treated mice than in the control mice, and there were decreased percentages of Th1 and Th17 cells in vivo. In addition, expression levels of the T-bet (Th1 transcription factor) and RORγt (Th17 transcription factor) genes were significantly downregulated by SPA treatment. Moreover, SPA reduced the production and mRNA expression of pro-inflammatory cytokine mRNAs in activated T cells in vivo. Mechanistically, SPA could inhibit STAT1/4 and STAT3 phosphorylation, resulting in the differentiation of Th1 and suppression of Th17 cells, respectively. In the presence of CD3/CD28 expression, STAT1/4 and STAT3 were activated but suppressed by SPA, which was responsible for the augmentation of Th1 and Th17 differentiation. This result showed that SPA can effectively modulate the JAK/STAT pathway by suppressing Th1 and Th17 differentiation, thus preventing asthma. The present study reveals the novel immunomodulatory activity of SPA and highlights the importance of further investigating the effects of SPA on asthma.
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Asma/metabolismo , Proteína A Asociada a Surfactante Pulmonar/farmacología , Transducción de Señal/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Asma/inducido químicamente , Asma/fisiopatología , Femenino , Quinasas Janus/metabolismo , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/efectos adversos , Factores de Transcripción STAT/metabolismo , Células TH1/metabolismo , Células Th17/metabolismoRESUMEN
Genes involved in latent membrane protein 1 (LMP1) signaling pathways have been suggested to play an important role in nasopharyngeal carcinogenesis. We investigated potentially functional genetic variants associated with the risk of nasopharyngeal carcinoma (NPC) in genes involved in the LMP1 signaling pathway. Altogether, 73 single nucleotide polymorphisms (SNPs) with MAF ≥ 10% were located within the regions of interest of the four genes TRAF3, NFKBIA, CHUK and MAP2K4. From these, 10 SNPs were selected for genotyping based on LD (r2 ≥ 0.80) in a hospital-based case-control study of 332 NPC cases and 585 healthy controls from the Chinese Han population. Minor allele carriers of the promoter SNP rs2233409 in NFKBIA, had an increased risk of NPC (AA vs GG: OR 7.14, 95%CI, 1.08-34.18, P = 0.04, dominant model). Based on the results, we concluded that rs2233409 polymorphism in NFKBIA may be moderately associated with the risk of NPC. Further studies with larger independent samples and functional analysis are needed to verify our results.
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Inhibidor NF-kappaB alfa/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Alelos , Pueblo Asiatico , Carcinogénesis/genética , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Quinasa I-kappa B/genética , MAP Quinasa Quinasa 4/genética , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/etnología , Neoplasias Nasofaríngeas/etnología , Regiones Promotoras Genéticas , Riesgo , Transducción de Señal , Factor 3 Asociado a Receptor de TNF/genética , Adulto JovenRESUMEN
BACKGROUND: Tuberculous pleural effusion (TPE) patients usually have elevated D-dimer levels. The diagnostic performance of D-dimer in predicting pulmonary embolism (PE) in the TPE population is unclear. This study aimed to assess the diagnostic performance of D-dimer for PE in the TPE population and explore its potential mechanism. METHODS: We retrospectively analysed patients who were admitted to Xinhua Hospital and Weifang Respiratory Disease Hospital with confirmed TPE between March 2014 and January 2020. D-dimer levels were compared between patients with and without PE. To test the diagnostic performance of D-dimer in predicting PE, receiver operating characteristic curve analysis was performed. Positive predictive value (PPV) and negative predictive value (NPV) were also reported. To explore the potential mechanism of PE in TPE, inflammatory biomarkers were compared between PE and non-PE patients. RESULTS: This study included 248 patients (170 males and 78 females) aged 43 ± 20.6 years. Elevated D-dimer levels (≥ 0.5 mg/L) were detected in 186/248 (75%) patients. Of the 150 patients who underwent computed tomography pulmonary angiography, 29 were diagnosed with PE. Among the TPE population, the PE patients had significantly higher D-dimer levels than the non-PE patients (median, 1.06 mg/L vs. 0.84 mg/L, P < 0.05). The optimal cut-off value for D-dimer in predicting PE in TPE was 1.18 mg/L, with a sensitivity of 89.7% and a specificity of 77.8% (area under curve, 0.893; 95% confidence interval 0.839-0.947; P < 0.01). The PPV was 49.1%, while the NPV was 96.9% at a D-dimer cut-off of 1.18 mg/L for PE. PE patients had lower median WBC and interleukin (IL)-8 values (5.14 × 109/L vs. 6.1 × 109/L, P < 0.05; 30.2 pg/ml vs. 89.7 pg/ml, P < 0.05) but a higher median IL-2 receptor value (1964.8 pg/ml vs. 961.2 pg/ml, P < 0.01) than those in the non-PE patients. CONCLUSIONS: D-dimer is an objective biomarker for predicting PE in patients with TPE. A D-dimer cut-off of 1.18 mg/L in the TPE population may reduce unnecessary radiological tests due to its excellent sensitivity, specificity, and NPV for PE. The imbalance of prothrombotic and antithrombotic cytokines may partly be attributed to the formation of pulmonary emboli in patients with TPE.
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Productos de Degradación de Fibrina-Fibrinógeno/análisis , Derrame Pleural/diagnóstico , Tuberculosis Pleural/diagnóstico , Adulto , Biomarcadores , Angiografía por Tomografía Computarizada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Adulto JovenRESUMEN
Idiopathic Pulmonary fibrosis(PF)is a chronic progressive disease, which is a lack of effective treatment,and the pathogenesis of IPF is not fully elucidated. Asiaticoside(AS) is isolated from Centella asiatica and has the effect of promoting scar healing and reducing scar formation. However,its possible role in idiopathic pulmonary fibrosis remains unclear. Adenosine A2A receptor (A2AR) is reported a protective factor in pulmonary fibrosis, and the bone morphogenetic protein 7 (BMP7) signaling pathway plays a crucial role in fibrosis in multiple organs. But the impact of A2AR on the BMP7 pathway has not yet been reported. Therefore, we hypothesized AS may promote the expression of A2AR, and then influence the BMP7/Smad1/5 pathway to alleviate pulmonary fibrosis. A2AR-/- mice and wild-type (WT) mice were administered bleomycin (BLM) by intratracheal injection. AS (50 mg/kg/d) was given daily for 28 days. AS reduced collagen deposition in lung tissue, interstitial lung inflammation. Furthermore, AS promoted A2AR expression and BMP7 pathway. Collectively, AS may attenuate BLM-induced pulmonary fibrosis by upregulating the BMP7 signaling pathway through A2AR.
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Proteína Morfogenética Ósea 7/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Receptor de Adenosina A2A/genética , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Triterpenos/uso terapéutico , Animales , Bleomicina , Centella/química , Eliminación de Gen , Masculino , Ratones , Ratones Endogámicos BALB C , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Triterpenos/químicaRESUMEN
The self-transportation of mobile Leidenfrost droplets with well-defined direction and velocity on millimetric ratchets is one of the most representative and spectacular phenomena in droplet dynamics. Despite extensive progress in the ability to control the spatiotemporal propagation of droplets, it remains elusive how the individual ratchet units, as well as the interactions within their arrays, are translated into the collective droplet dynamics. Here, simple planar ratchets characterized by uniform height normal to the surface are designed. It is revealed that on planar ratchets, the transport dynamics of Leidenfrost droplets is dependent not only on individual units, but also on the elegant coordination within their arrays dictated by their topography. The design of planar ratchets enriches the fundamental understanding of how the surface topography is translated into dynamic and collective droplet transport behaviors, and also imparts higher applicability in microelectromechanical system based fluidic devices.
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BACKGROUND: Since December 2019, the outbreak of COVID-19 caused a large number of hospital admissions in China. Many patients with COVID-19 have symptoms of acute respiratory distress syndrome, even are in danger of death. This is the first study to evaluate dynamic changes of D-Dimer and Neutrophil-Lymphocyte Count Ratio (NLR) as a prognostic utility in patients with COVID-19 for clinical use. METHODS: In a retrospective study, we collected data from 349 hospitalized patients who diagnosed as the infection of the COVID-19 in Wuhan Pulmonary Hospital. We used ROC curves and Cox regression analysis to explore critical value (optimal cut-off point associated with Youden index) and prognostic role of dynamic changes of D-Dimer and NLR. RESULTS: Three hundred forty-nine participants were enrolled in this study and the mortality rate of the patients with laboratory diagnosed COVID-19 was 14.9%. The initial and peak value of D-Dimer and NLR in deceased patients were higher statistically compared with survivors (P < 0.001). There was a more significant upward trend of D-Dimer and NLR during hospitalization in the deceased patients, initial D-Dimer and NLR were lower than the peak tests (MD) -25.23, 95% CI: - 31.81- -18.64, P < 0.001; (MD) -43.73, 95% CI:-59.28- -31.17, P < 0.001. The test showed a stronger correlation between hospitalization days, PCT and peak D-Dimer than initial D-Dimer. The areas under the ROC curves of peak D-Dimer and peak NLR tests were higher than the initial tests (0.94(95%CI: 0.90-0.98) vs. 0.80 (95% CI: 0.73-0.87); 0.93 (95%CI:0.90-0.96) vs. 0.86 (95%CI:0.82-0.91). The critical value of initial D-Dimer, peak D-Dimer, initial NLR and peak NLR was 0.73 mg/L, 3.78 mg/L,7.13 and 14.31 respectively. 35 (10.03%) patients were intubated. In the intubated patients, initial and peak D-Dimer and NLR were much higher than non-intubated patients (P < 0.001). The critical value of initial D-Dimer, peak D-Dimer, initial NLR and peak NLR in prognosticate of intubation was 0.73 mg/L, 12.75 mg/L,7.28 and 27.55. The multivariable Cox regression analysis showed that age (HR 1.04, 95% CI 1.00-1.07, P = 0.01), the peak D-Dimer (HR 1.03, 95% CI 1.01-1.04, P < 0.001) were prognostic factors for COVID-19 patients' death. CONCLUSIONS: To dynamically observe the ratio of D-Dimer and NLR was more valuable during the prognosis of COVID-19. The rising trend in D-Dimer and NLR, or the test results higher than the critical values may indicate a risk of death for participants with COVID-19.
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Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/epidemiología , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Recuento de Linfocitos , Neutrófilos , Neumonía Viral/sangre , Neumonía Viral/epidemiología , Adulto , Anciano , Biomarcadores/sangre , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/diagnóstico , Femenino , Hospitales Especializados , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tasa de SupervivenciaRESUMEN
x-membered lactams were synthesized via either an amidation of sp3 C-H bonds or an electrophilic substitution of arenes via Ir-nitrene intermediates. With the employment of a readily available iridium catalyst in dichloromethane or hexafluoro-2-propanol, a wide range of lactams were synthesized in good to excellent yields with high selectivity.
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C-Glycosylation reactions of glycosyl picolinates with allyltrimethylsilane or silyl enol ethers were developed. Picolinate as a chelation-assisted leaving group could be activated by Cu(OTf)2 and avoided the use of harsh Lewis acids. The glycosylations were operated under mild neutral conditions and gave the corresponding C-glycosides in up to 95% yield with moderate to excellent stereoselectivities.