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1.
Clin Lung Cancer ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34645582

RESUMO

BACKGROUND: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. METHOD: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1PE-sDNA. RESULT: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. CONCLUSION: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.

2.
Drug Dev Res ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609751

RESUMO

Th2 and Th17 immune response contribute to allergic rhinitis (AR) development. Targeting Th2 and Th17 response has been shown to ameliorate AR. Ibrutinib is an inhibitor for IL2-inducible T-cell kinase, which can promote Th2 and Th17 immune response. We sought to investigate the effect of ibrutinib on AR and the underlying mechanisms. We established house dust mite-induced AR mouse model and treated AR mice with ibrutinib. The symptoms of AR, serum level of immunoglobulin E, percentage of Th1, Th2, Th17, and Treg in nasal lymphoid tissues were monitored. We also established in vitro T cell differentiation cell culture model. The T cells were treated with ibrutinib and the expression of specific transcriptional factors and cytokines was measured. The activation of PLC-γ1/calcium/NFAT2 signaling pathway was detected. Ibrutinib treatment had no effects on the development of lymphocytes and myeloid cells, but alleviated AR symptoms and decreased Th2 cell population in nasal lymphoid tissue. Meanwhile, iburitnib suppressed Th2 and Th17 differentiation in vitro. Moreover, iburitnib prevented phosphorylation of PLC-γ1and nuclear translocation of NFAT2 in Th2 cells. Our results suggested that ibrutinib could ameliorate AR symptoms through suppression of Th2 differentiation in AR mouse model.

3.
Disabil Rehabil ; : 1-8, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623949

RESUMO

PURPOSE: To evaluate the psychometric properties of the Chinese Fear of Cancer Recurrence Inventory (FCRI-C) in follicular lymphoma (FL) survivors. MATERIALS AND METHODS: A nationwide cross-sectional study was conducted online between July and September 2020. The following psychometric properties of the FCRI-C were evaluated: construct, convergent, and discriminant validity, and reliability. Item variance was assessed using differential item functioning (DIF). A short version of the FCRI-C was developed using a two-parameter item response theory (IRT) model. The patterns of response scale, item fit, and item information were assessed. The receiver operating characteristic (ROC) curve was used to determine the clinical cut-off point for the FCRI-C. RESULTS: A total of 326 FL survivors completed the questionnaire. The confirmatory factor analysis supported the bi-factor structure of the FCRI-C. The IRT analysis confirmed a 10-item short version of the FCRI-C. Satisfactory convergent and discriminant validity were underpinned by a priori hypotheses. Cronbach's alpha of 0.95 and intraclass correlation coefficient of 0.82 indicated good internal consistency and test-retest reliability. The ROC curve determined a cut-off point of 83 and 20 for the full and short versions, respectively. CONCLUSIONS: The FCRI-C used to measure and screen the levels of FCR in Chinese FL survivors was found to be valid and reliable.Implications for RehabilitationThe Chinese Fear of Cancer Recurrence Inventory (FCRI-C) is a reliable and valid measure to evaluate the fear of cancer recurrence (FCR) in follicular lymphoma survivors.The short version of the FCRI-C provides a rapid screening tool for the clinical detection of FCR in patients.The cut-off point of the FCRI-C could differentiate patients between "high" and "low" levels of FCR in clinical practice.

4.
Ups J Med Sci ; 1262021.
Artigo em Inglês | MEDLINE | ID: mdl-34471485

RESUMO

Background: Hirschsprung's disease (HSCR) is a common defect in newborns, and studies have revealed that long non-coding RNA (lncRNA) is involved in the progression of HSCR. This research study aims to investigate the mechanism of downregulated RNA in cancer (DRAIC) on cell proliferation and migration in HSCR. Methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the expression of DRAIC in HSCR bowel stenosis tissues and normal colon tissues. Cell-counting kit-8 (CCK-8) and Transwell assays were employed to explore whether cellular functions change after overexpression or knockdown of the DRAIC in SH-SY5Y cells and human 293T cells. Protein expression levels were determined by Western blot analysis. RNA pull-down and dual-luciferase reporter assays were used to confirm the competitive relationship of DRAIC and integrin subunit alpha 6 (ITGA6) through their association with miR-34a-5p. Results: The lncRNA DRAIC was significantly increased in colon tissue from HSCR patients. The overexpression of DRAIC inhibited SH-SY5Y cell and human 293T cell proliferation and migration. Knockdown of DRAIC, however, promoted cell proliferation and migration. The RNA pull-down and dual-luciferase reporter assays have proven the competitive relationship between DRAIC and ITGA6 through their association with miR-34a-5p. Further rescue experiments have confirmed that DRAIC regulates cell proliferation and migration by affecting the miR-34a-5p/ITGA6 signal axis in HSCR. Conclusion: DRAIC promoted cell proliferation and migration by regulating the miR-34a-5p/ITGA6 signal axis in HSCR.

5.
J Am Chem Soc ; 143(38): 15852-15862, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34528792

RESUMO

Tumorigenic risk of undifferentiated human induced pluripotent stem cells (iPSCs), being a major obstacle for clinical application of iPSCs, requires novel approaches for selectively eliminating undifferentiated iPSCs. Here, we show that an l-phosphopentapeptide, upon the dephosphorylation catalyzed by alkaline phosphatase (ALP) overexpressed by iPSCs, rapidly forms intranuclear peptide assemblies made of α-helices to selectively kill iPSCs. The phosphopentapeptide, consisting of four l-leucine residues and a C-terminal l-phosphotyrosine, self-assembles to form micelles/nanoparticles, which transform into peptide nanofibers/nanoribbons after enzymatic dephosphorylation removes the phosphate group from the l-phosphotyrosine. The concentration of ALP and incubation time dictates the morphology of the peptide assemblies. Circular dichroism and FTIR indicate that the l-pentapeptide in the assemblies contains a mixture of an α-helix and aggregated strands. Incubating the l-phosphopentapeptide with human iPSCs results in rapid killing of the iPSCs (=<2 h) due to the significant accumulation of the peptide assemblies in the nuclei of iPSCs. The phosphopentapeptide is innocuous to normal cells (e.g., HEK293 and hematopoietic progenitor cell (HPC)) because normal cells hardly overexpress ALP. Inhibiting ALP, mutating the l-phosphotyrosine from the C-terminal to the middle of the phosphopentapeptides, or replacing l-leucine to d-leucine in the phosphopentapeptide abolishes the intranuclear assemblies of the pentapeptides. Treating the l-phosphopentapeptide with cell lysate of normal cells (e.g., HS-5) confirms the proteolysis of the l-pentapeptide. This work, as the first case of intranuclear assemblies of peptides, not only illustrates the application of enzymatic noncovalent synthesis for selectively targeting nuclei of cells but also may lead to a new way to eliminate other pathological cells that express a high level of certain enzymes.

6.
Soft Matter ; 17(38): 8590-8594, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34545895

RESUMO

Enzyme-instructed self-assembly (EISA) and hydrogelation is a versatile approach for generating soft materials. Most of the substrates for alkaline phosphatase catalysed EISA utilize phosphotyrosine (pTyr) as the enzymatic trigger for EISA and hydrogelation. Here we show the first example of phosphonaphthyl (pNP) and phosphobiphenyl (pBP) motifs acting as faster enzymatic triggers than phosphotyrosine for EISA and hydrogelation. This work illustrates novel enzyme triggers for rapid enzymatic self-assembly and hydrogelation.


Assuntos
Hidrogéis , Peptídeos , Hidrogéis/química , Hidrogéis/metabolismo , Peptídeos/química , Peptídeos/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-34545677

RESUMO

A bis(pyridyl)amine-bipyridine-iron(II) framework (Fe(BPAbipy)) of complexes 1-3 is reported to shed light on the multistep nature of CO 2 reduction. Herein, photocatalytic conversion of CO 2 to CO even at low CO 2 concentration (1%), together with detailed mechanistic study and DFT calculations, reveal that 1 first undergoes two sequential one-electron transfer affording an intermediate with electron density on both Fe and ligand for CO 2 binding over proton. The following 2H + -assisted Fe-CO formation is rate-determining for selective CO 2 -to-CO reduction. A pendant, proton-shuttling α-OH group ( 2 ) initiates PCET for predominant H 2 evolution, while an α-OMe group ( 3 ) cancels the selectivity control for either CO or H 2 . The near-unity selectivity of 1 and 2 enables self-sorting syngas production at flexible CO/H 2 ratios. The unprecedented results from one kind of molecular catalyst skeleton encourage insight into the beauty of advanced multi-electron and multi-proton transfer processes for robust CO 2 RR by photocatalysis.

9.
Environ Sci Technol ; 55(17): 11557-11567, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34431667

RESUMO

The lockdown due to COVID-19 created a rare opportunity to examine the nonlinear responses of secondary aerosols, which are formed through atmospheric oxidation of gaseous precursors, to intensive precursor emission reductions. Based on unique observational data sets from six supersites in eastern China during 2019-2021, we found that the lockdown caused considerable decreases (32-61%) in different secondary aerosol components in the study region because of similar-degree precursor reductions. However, due to insufficient combustion-related volatile organic compound (VOC) reduction, odd oxygen (Ox = O3 + NO2) concentration, an indicator of the extent of photochemical processing, showed little change and did not promote more decreases in secondary aerosols. We also found that the Chinese provinces and international cities that experienced reduced Ox during the lockdown usually gained a greater simultaneous PM2.5 decrease than other provinces and cities with an increased Ox. Therefore, we argue that strict VOC control in winter, which has been largely ignored so far, is critical in future policies to mitigate winter haze more efficiently by reducing Ox simultaneously.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Aerossóis/análise , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/prevenção & controle , China , Controle de Doenças Transmissíveis , Monitoramento Ambiental , Humanos , Oxigênio , Material Particulado/análise , SARS-CoV-2
10.
J Hematol Oncol ; 14(1): 131, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425858

RESUMO

Clinical features and outcomes of FL patients in Chinese population are limited, thus promoting us to perform this analysis on a large cohort of 1845 patients with FL enrolled from nine medical centers nationwide in China. In this cohort, the median age of patients at diagnosis was 53 years, which was comparable to that reported previously for Chinese FL patients (49-51 years) but younger than that for Western FL patients (60-65 years). In contrast with Western patients, Chinese FL patients more likely involved extranodal sites but less frequently infiltrated bone marrow. Other clinical characteristics were comparable between two populations. In this study, 91% of patients were managed with chemotherapy, yielding 72% and 46% of overall-response rate and complete remission. After median 55-month follow-up, 5-year progressive-free and overall survival were 61% and 89%, respectively. Both were analogous to those reported in prior Chinese and Western studies. Consistent with published data, addition of rituximab into both induction (Ri) and maintenance (Rm) treatment led to the most favorable outcomes. Interestingly, Ri only had better outcomes than Rm only. Notably, 7% of patients experienced histologic transformation (HT) and correlated with poor survival. Of the transformed FL cases, 3% and 4% of HT events occurred prior to or post-treatment, respectively. Importantly, the latter displayed worse outcomes than the former. Altogether, this study provides real-world information of the largest cohort of FL patients so far in China, which might lay a foundation for clinical investigation of Chinese FL in future.

11.
Sci Rep ; 11(1): 17012, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426610

RESUMO

The secretory carrier-associated membrane proteins (SCAMPs) are associated with the development of multiple human cancers. The role of SCAMPs in acute myeloid leukemia (AML), however, remains to be identified. In the present study, we explored expression patterns and prognostic value of SCAMPs and network analysis of SCAMPs-related signaling pathways in AML using Oncomine, GEPIA, cBioPortal, LinkedOmics, DAVID and Metascape databases. Genetic alteration analysis revealed that the mutation rate of SCAMP genes was below 1% (9/1272) in AML, and there was no significant correlation between SCAMPs gene mutation and AML prognosis. However, the SCAMP2/5 mRNA levels were significantly higher in AML patients than in healthy controls. Moreover, high mRNA expressions of SCAMP2/4/5 were associated with poor overall survival, which might be due to that SCAMP2/4/5 and their co-expressed genes were associated with multiple pathways related to tumorigenesis and progression, including human T-cell leukemia virus 1 infection, acute myeloid leukemia, mTOR and NF-kappa B signaling pathways. These results suggest that SCAMP2/4/5 are potential prognostic markers for AML, and that SCAMP2 and SCAMP5 individually or in combination may be used as diagnostic markers for AML.

12.
Blood ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34411225

RESUMO

Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) are highly efficacious for patients with multiple myeloma (MM). However, relapses are frequent and acquired resistance to PI treatment emerges in most patients. Here we performed a high-throughput screen of 1855 FDA-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and re-sensitized Cfz-resistant MM cells to Cfz in vitro. ATRA activated RARγ and IFN-ß response pathway, leading to upregulated expression of IRF1. IRF1 in turn initiated the transcription of OAS1, which synthesized 2-5A upon binding to dsRNA induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death. Similar to ATRA, BMS961, a selective RARγ agonist, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo. In support of these findings, analyses of large patient's gene-profiling datasets showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment. Thus, this study highlights the potential for RARγ agonists to sensitize and overcome MM resistance to Cfz treatment in patients.

13.
Sci Rep ; 11(1): 16514, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389766

RESUMO

High shear wet granulation (HSWG) has been wildly used in manufacturing of oral solid dosage (OSD) forms, and process modeling is vital to understanding and controlling this complex process. In this paper, data fusion and multivariate modeling technique were applied to develop a formulation-process-quality model for HSWG process. The HSWG experimental data from both literature and the authors' laboratory were fused into a single and formatted representation. A material database and material matching method were used to compensate the incomplete physical characterization of literature formulation materials, and dimensionless parameters were utilized to reconstruct process variables at different granulator scales. The exploratory study on input materials properties by principal component analysis (PCA) revealed that the formulation data collected from different articles generated a formulation library which was full of diversity. In prediction of the median granule size, the partial least squares (PLS) regression models derived from literature data only and a combination of literature data and laboratory data were compared. The results demonstrated that incorporating a small number of laboratory data into the multivariate calibration model could help significantly reduce the prediction error, especially at low level of liquid to solid ratio. The proposed data fusion methodology was beneficial to scientific development of HSWG formulation and process, with potential advantages of saving both experimental time and cost.

14.
Oncoimmunology ; 10(1): 1928365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350060

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.

15.
Eur J Cancer ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34462189

RESUMO

BACKGROUND: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). METHODS: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). RESULTS: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. CONCLUSIONS: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.

16.
J Environ Manage ; 298: 113403, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34365183

RESUMO

Our paper proposes a novel measure of global energy market uncertainty and studies its impact on oil prices. The current literature primarily relies on a single or small number of observable variables, or general macroeconomic uncertainty (JLN) and economic policy uncertainty (EPU) indices to reflect energy market uncertainty. Using a Factor Augmented Vector Autoregression model (FAVAR), we construct time-varying global energy market uncertainty in a data-rich environment. Our estimates show variations from JLN and EPU proxies. The results reveal that real oil prices respond strongly to our proposed aggregate energy market uncertainty shocks. We also find heterogeneous responses to different types and magnitudes of uncertainty shocks. The real price of oil is affected the most under unexpected strong demand for alternative energy sources scenario.


Assuntos
Petróleo , Incerteza
17.
J Craniomaxillofac Surg ; 49(9): 830-836, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34218975

RESUMO

The study aimed at investigating a new three-dimensional classification of healing morphology in condylar fractures in children and adolescents after closed treatment, and establish its association with fracture type and clinical outcomes. The medical records of children and adolescents with condylar fracture were reviewed, retrospectively. The clinical outcomes were assessed by mandibular deviation during mouth opening, Helkimo anamnestic index (Ai), and Helkimo clinical dysfunction index (Di). The condylar healing morphology was evaluated through three-dimensional CT images after 1-2 years of follow-up. In total, 96 patients with 142 condylar fracture sites were included in the study. Condylar healing morphology was classified into three main patterns: unchanged (21.13%), spherical (62.68%), and irregular (16.19% - including the three subtypes triangular, L-shaped, and Y-shaped). There was a significant difference in the distribution of the three main healing patterns among various fracture types (p = 0.0227). Irregular patterns occurred more frequently in adolescents than in children. In unilateral fractures, no obvious association was found between condylar healing morphology and clinical outcomes, including mandibular deviation during mouth opening (p = 0.162), Ai (p = 0.0991) and Di (p = 0.25). Most patients healing in different condylar patterns reached a good clinical outcome after 1-2 years. Although the healing morphology of condylar fractures in children and adolescents remained abnormal, good clinical outcome was achieved over the 2-year follow-up. Therefore, closed treatment remains a good approach.


Assuntos
Fraturas Mandibulares , Adolescente , Criança , Fixação Interna de Fraturas , Humanos , Côndilo Mandibular/diagnóstico por imagem , Fraturas Mandibulares/diagnóstico por imagem , Fraturas Mandibulares/terapia , Estudos Retrospectivos , Resultado do Tratamento
18.
Artigo em Inglês | MEDLINE | ID: mdl-34321387

RESUMO

PURPOSE: Pulmonary parenchyma saving method (cystotomy and enucleation) has been globally accepted in lung hydatidosis. However, whether capitonnage is performed or not after cystotomy is still controversial. This study aims to improve the diagnosis and treatment of patients. METHODS: We retrospectively analyzed the data of 12 pediatric patients with pulmonary hydatid cysts. These 12 patients (10 males and 2 females), with an average age of 8.7 years, underwent cystotomy without capitonnage. The mean follow-up period was 36 months. RESULTS: Among the 12 patients, 10 underwent thoracotomy cystotomy and 2 underwent thoracoscopic surgery with excellent outcomes except one case of postoperative broncho-pleura fistula, which was treated through thoracoscopic surgery. The mean hospital stay was 8 days. No death or recurrence occurred during the follow-up period. CONCLUSION: Good therapeutic effect can be expected by combining cystotomy of pulmonary hydatid cysts with postoperative anti-hydatid drug therapy. For those unruptured (uncomplicated) hydatid lung cysts, cystotomy with the non-capitonnage method seems to be the best option, which needs to be verified by well-designed studies.

19.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205464

RESUMO

BACKGROUND: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic-ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. METHODS: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. RESULTS: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r2 = 0.61, p < 0.05) and CA1/2 hippocampal region (r2 = 0.66, p < 0.05). CONCLUSION: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.


Assuntos
Aminoquinolinas/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Imidazóis/uso terapêutico , Convulsões/prevenção & controle , Receptor 7 Toll-Like/agonistas , Aminoquinolinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Eletroencefalografia , Feminino , Terapias Fetais/métodos , Hipóxia-Isquemia Encefálica/complicações , Imidazóis/farmacologia , Gravidez , Nascimento Prematuro , Convulsões/etiologia , Ovinos
20.
Ying Yong Sheng Tai Xue Bao ; 32(6): 2021-2027, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34212607

RESUMO

A method for geographical discrimination of Portunus trituberculatus was explored to provide technical support for the protection of geographical indication products and for tracing the origin of seafood. P. trituberculatus were collected from three major production areas, including the Yellow Sea, the Bohai Sea, and the East China Sea. The variations of carbon and nitrogen stable isotope values of origins and the correlation of stable isotope ratios in different tissues were analyzed. The results showed that there were significant differences in carbon and nitrogen stable isotope ratio among different origins. Significant isotope fractionation effects were observed among different tissues. The discriminant model was developed and the origin discriminant analysis was performed by the stable isotope ratios of different tissues in P. trituberculatus. The correct rate of origin diffe-rentiationf using carbon and nitrogen stable isotopes in muscle and gills (>95%) was significantly higher than that of hepatopancreas and gonad, indicating that stable isotope ratios of muscle and gills could effectively differentiate P. trituberculatus in different sea areas. This study filled the gap of stable isotope tracing technology for P. trituberculatus.


Assuntos
Braquiúros , Animais , Isótopos de Carbono/análise , China , Hepatopâncreas/química , Nitrogênio , Isótopos de Nitrogênio/análise
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