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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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An axion insulator is a correlated topological phase, which is predicted to arise from the formation of a charge-density wave in a Weyl semimetal1,2-that is, a material in which electrons behave as massless chiral fermions. The accompanying sliding mode in the charge-density-wave phase-the phason-is an axion3,4 and is expected to cause anomalous magnetoelectric transport effects. However, this axionic charge-density wave has not yet been experimentally detected. Here we report the observation of a large positive contribution to the magnetoconductance in the sliding mode of the charge-density-wave Weyl semimetal (TaSe4)2I for collinear electric and magnetic fields. The positive contribution to the magnetoconductance originates from the anomalous axionic contribution of the chiral anomaly to the phason current, and is locked to the parallel alignment of the electric and magnetic fields. By rotating the magnetic field, we show that the angular dependence of the magnetoconductance is consistent with the anomalous transport of an axionic charge-density wave. Our results show that it is possible to find experimental evidence for axions in strongly correlated topological condensed matter systems, which have so far been elusive in any other context.
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OBJECTIVE: Acute intracerebral hemorrhage (AICH) and cerebral cavernous hemangioma (CCM) are two common cerebral hemorrhage diseases with partially overlapping CT findings and clinical symptoms, making it hard to distinguish between them. The current study used histogram analysis based on CT images to differentiate between CCM and AICH and test its diagnosis performance. METHODS: This retrospective study included 158 patients with CCM and 137 patients with AICH. The histograms of brain CT plain scan images of both groups were extracted using Python code and included 18 histogram parameters of the lesions. The most effective parameters were selected by univariate logistic regression analysis and Spearman correlation analysis and included in the final multivariate logistic regression model. The sample was randomly divided into the training set and the validation set by 7:3. The ROC curve was constructed to evaluate the discriminant efficiency of the final logistic regression model in distinguishing between AICH and CCM. RESULTS: The univariate analysis identified seven significant histogram parameters with the following final logistic regression model: F = 3.731 + 2.6411 × 10-9 × Energy-1.192 × Kurtosis-0.003 × Minimum-1.449 × Skewness + 2.5002 × 10-10 × Total Energy-1.103 × Uniformity+0.009 × Variance. The model showed good diagnostic performance in distinguishing between AICH and CCM, with an AUC of 0.876, sensitivity of 70.8%, and specificity of 91.9% in the training set, and an AUC of 0.870, sensitivity of 82.9%, and specificity of 85.1% in the validation set. CONCLUSIONS: The histogram analysis of brain CT images can be used as an auxiliary method to distinguish between AICH and CCM effectively.
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INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization. METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling. RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways. DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity. HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.
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1. This study focused on the relationship between MITF mRNA expression and plumage colour in quail and the effect of promoter methylation on the expression of MITF mRNA.2. The CDS region of MITF mRNA was cloned by RT-PCR, followed by DNA sequencing. The RT-qPCR method was used to analyse the expression levels of MITF mRNA in dorsal skin tissue in Korean quail and Beijing white quail. The promoter region of the MITF gene was cloned, and the CpG island was predicted by the CpGplot program. The methylation levels of the CpG island were analysed using BS-PCR technology.3. Quail MITF mRNA contains a 1,476 bp complete ORF, which encodes a 492 amino acid residue protein. The MITF protein has no signal peptide or transmembrane region. The expression of MITF mRNA in dorsal tissue of Korean quail was significantly higher than that in Beijing white quail (p < 0.01). Abundant cis-elements and a 346 bp CpG island were found in the promoter region of the MITF gene. The average methylation level of the CpG island was 22 (22%) in Korean quail, and 46 (30%) in Beijing white quail (p < 0.05).4. The hypermethylation of the MITF gene promoter region in Beijing white quail resulted in a decrease in expression level, which was related to white feather colour.
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Coturnix , Ilhas de CpG , Metilação de DNA , Plumas , Fator de Transcrição Associado à Microftalmia , Pigmentação , Regiões Promotoras Genéticas , Animais , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Plumas/química , Coturnix/genética , Coturnix/metabolismo , Coturnix/fisiologia , Pigmentação/genética , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Expressão Gênica , Sequência de Bases , Sequência de Aminoácidos , MasculinoRESUMO
Objective: To investigate the role of an inflammatory microenvironment induced by Porphyromonasgingivalis (P. gingivalis) in the occurrence of esophageal squamous cell carcinoma (ESCC) in mice. Methods: A total of 180 C57BL/6 mice were randomly divided into 6 groups, i.e. control group, P. gingivalis group, 4NQO group, 4NQO + P. gingivalis group, 4NQO + P. gingivalis + celecoxib group, and 4NQO + P. gingivalis + antibiotic cocktail (ABC, including metronidazole, neomycin, ampicillin, and vancomycin) group, with 30 mice in each group, using the random number table. All mice were normalized by treatment with ABC in drinking water for 2 weeks. In the following 2 weeks, the mice in the control group and the P. gingivalis group were given drinking water, while the other 4 groups were treated with 30 µg/ml 4NQO in the drinking water. In weeks 11-12, the mice in the P. gingivalis group, the 4NQO + P. gingivalis group, the 4NQO + P. gingivalis + celecoxib group, and the 4NQO + P. gingivalis + ABC group were subjected to ligation of the second molar in oral cavity followed by oral P. gingivalis infection thrice weekly for 24 weeks in weeks 11-34. In weeks 13-34, the mice in 4NQO + P. gingivalis+celecoxib group and 4NQO + P. gingivalis + ABC group were administered with celecoxib and ABC for 22 weeks, respectively. At the end of 34 weeks, gross and microscopic alterations were examined followed by RT-qPCR and immunohistochemistry to examine the expression profiles of inflammatory- and tumor-molecules in esophagi of mice. Results: At 34 weeks, 4NQO treatment alone did not affect the foci of papillary hyperproliferation, diseased area, and the thickness of the esophageal wall, but significantly enhanced the foci of hyperproliferation (median 1.00, Pï¼0.05) and mild/moderate dysplasia (median 2.00, Pï¼0.01). In addition, the expression levels of IL-6 [8.35(3.45,8.99)], IL-1ß [6.90(2.01,9.72)], TNF-α [12.04(3.31,14.08)], c-myc [2.21(1.80,3.04)], pSTAT3, Ki-67, and pH2AX were higher than those in the control group. The pathological changes of the esophageal mucosa were significantly more overt in the 4NQO + P. gingivalis group in terms of the foci of papillary hyperproliferation (median 2.00), diseased area (median 2.51 mm2), the thickness of the esophageal wall (median 172.52 µm), the foci of hyperproliferation (median 1.00, Pï¼0.05), and mild/moderate dysplasia (median 1.00, Pï¼0.01). In mice of the 4NQO + P. gingivalis group, the expression levels of IL-6 [12.27(5.35,22.08)], IL-1ß [13.89(10.04,15.96)], TNF-α [19.56(6.07,20.36)], IFN-γ [11.37(8.23,20.07)], c-myc [2.62(1.51,4.25)], cyclin D1 [4.52(2.68,7.83)], nuclear pSTAT3, COX-2, Ki-67, and pH2AX were significantly increased compared with the mice in the control group. In mice of the 4NQO + P. gingivalis group, the diseased area, invasive malignant foci as well as pSTAT3 and pH2AX expression were significantly blunted by celecoxib. Treatment with ABC markedly reduced the papillary hyperproliferative foci, invasive malignant foci, and pSTAT3 expression but not pH2AX. Conclusions: P. gingivalis promotes the occurrence of esophageal squamous cell carcinoma in mice by inducing an inflammatory microenvironment primed with 4NQO induced DNA damage. Clearance of P. gingivalis with ABC or anti-inflammatory intervention holds promise for prevention of esophageal squamous cell malignant pathogenesis via blockage of IL-6/STAT3 signaling and amelioration of inflammation.
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4-Nitroquinolina-1-Óxido , Celecoxib , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Camundongos Endogâmicos C57BL , Porphyromonas gingivalis , Microambiente Tumoral , Animais , Camundongos , Neoplasias Esofágicas/microbiologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/microbiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Celecoxib/farmacologia , Inflamação , Infecções por Bacteroidaceae/microbiologia , Interleucina-6/metabolismo , Antibacterianos/farmacologia , Fator de Transcrição STAT3/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Esôfago/microbiologia , Esôfago/patologia , Esofagite/microbiologia , Esofagite/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Carcinoma de Células Escamosas/microbiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismoRESUMO
Objective: To investigate the clinical characteristics of children with early-onset necrotizing enterocolitis (NEC) undergoing enterostomy and analyze the risk factors for postoperative complications. Methods: Retrospective analysis was conducted on the clinical data (perinatal conditions, clinical characteristics, clinical outcomes, etc.) of NEC patients who underwent enterostomy at Beijing Children's Hospital from May 2016 to May 2023. The patients were divided into two groups based on the age of onset: an early-onset enterostomy group (<14 days) and a late-onset enterostomy group (≥14 days). Furthermore, the children with NEC were categorized into complication group and non-complication group based on whether there were complications after enterostomy. The differences in clinical data between these groups were analyzed, and the clinical characteristics of children with early-onset NEC and enterostomy were summarized. Multivariate logistic regression model was employed to analyze the risk factors for postoperative complications in NEC children with enterostomy. Results: A total of 68 cases were enrolled, including 43 cases in the early-onset enterostomy group [26 males and 17 females, aged (6.5±3.0) days] and 25 cases in the late-onset enterostomy group [15 males and 10 females, aged (21.0±3.0) days]. There were 28 cases (17 males and 11 females), age [M (Q1, Q3)] 9 (5, 14) days in the complication group and 33 cases (22 males and 11 females), aged of 14 (6, 21) days in the non-complication group. Compared to the late-onset enterostomy group, the early-onset enterostomy group had significantly higher rates of intraventricular hemorrhage [30.2% (13/43) vs 8.0% (2/25)], hemodynamically significant patent ductus arteriosus [37.2% (16/43) vs 12.0% (3/25)], mechanical ventilation≥72 hours after birth [39.5% (17/43) vs 16.0% (4/25)], stage â ¢ NEC [(69.8% (30/43) vs 40.0% (10/25)], extensive NEC [27.9% (12/43) vs 8.0% (2/25)], and short-term postoperative complications [56.8% (21/37) vs 29.2% (7/24)] (all P<0.05).Multivariate logistic regression model analysis revealed that residual length of proximal small intestine was a protective factor for postoperative complications after enterostomy in NEC infants (OR=0.764, 95%CI: 0.648-0.901, P=0.001), but stage â ¢ NEC was a risk factor (OR=1.042, 95%CI: 1.004-5.585, P=0.017). Conclusions: The incidence of postoperative complications is high, and the prognosis is poor in children with early-onset NEC enterostomy. The residual length of proximal enterostomy is a protective factor for postoperative complications of NEC enterostomy, but stage â ¢ NEC is a risk factor.
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Enterocolite Necrosante , Enterostomia , Doenças Fetais , Doenças do Recém-Nascido , Masculino , Lactente , Feminino , Criança , Recém-Nascido , Humanos , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/cirurgia , Estudos Retrospectivos , Enterostomia/efeitos adversos , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/cirurgia , Doenças Fetais/etiologia , Doenças Fetais/cirurgia , Complicações Pós-Operatórias/epidemiologia , Fatores de RiscoRESUMO
The list of occupational diseases reflecting the latest advances in the identification and recognition of occupational diseases, and providing guidance on the protection of workers' health rights and interests and the prevention, recording, notification and compensation of related occupational diseases. Diagnostic criteria for occupational diseases are an important basis for making diagnoses attributable to occupational diseases, and provide a theoretical basis for health monitoring of occupational groups and occupational hygiene supervision. This thesis starts with the definition of the occupational disease elaborates in detail the development history of list of occupational diseases in International Labour Organization (ILO) , compares the list of occupational diseases in China (2013 version) with the list of occupational diseases in international (2010 version) , and then introduces in detail the latest diagnostic standards of the major occupational diseases. And finally, it puts forward relevant suggestions on the list and diagnostic level of China's occupational diseases, so as to provide certain insights for the further improvement of the list and diagnostic standards of occupational diseases.
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Doenças Profissionais , Humanos , Doenças Profissionais/diagnóstico , China , Saúde OcupacionalRESUMO
Objective: To analyse the genetic cause of a proband with mitochondrial disease caused by FASTKD2 gene variation and uniparental disomy. Methods: Detailed medical history of a child suspected "mitochondrial disease" were inquired in Peking University First Hospital on November 23, 2017. c.810_820dup homozygous variation in FASTKD2 gene was found by high-throughput sequencing, and her mother had heterozygous variation, but her father didn't have such variation, which didn't conform to the genetic law of variation. Further clinical examinations and molecular genetic tests were carried out. The venous blood of the child and her parents was drawn, and genomic DNA was extracted. Sanger sequencing, polymerase chain reaction (PCR) testing, short tandem repeat (STR) analysis, chromosome microarray analysis and loss of heterozygosity (LOH) genetic relationship analysis were performed on the proband and the parents to determine the variation. Results: The clinical manifestations, physical examination and laboratory examination of the child supported the diagnosis of mitochondrial disease. c.810_820dup(p.Ser274Phefs*8) homozygous variant in FASTKD2 gene was identified. Sanger sequencing indicated that the mother was a heterozygote of the variant, while the father had no such variation, which did not conform to the genetic law. PCR testing and Sanger sequencing review to eliminate sampling errors, PCR amplification and sequencing errors. Non-biological father was excluded by STR analysis. Three large segmental LOH of FASTKD2 gene were found by chromosome microarray analysis, then the LOH relative analysis verified the child was a mixed maternal uniparental disomy of chromosome 2. The child was diagnosed as mitochondrial disease caused by oxidative phosphorylation coupling defect of type 44. Conclusions: In this study, an autosomal recessive mitochondrial disease which does not conform to the genetic law was found, and it was confirmed that this mitochondrial disease family had both pathogenic variation and uniparental disomy phenomenon. It was diagnosed as mitochondrial disease caused by type 44 oxidative phosphorylation coupling defect.
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Doenças Mitocondriais , Dissomia Uniparental , Criança , Feminino , Humanos , Heterozigoto , Homozigoto , Linhagem , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Objective: To analyze high-risk factors affecting BK polyomavirus (BKPyV) infection and to construct a prediction model for BKPyV infection in children after renal transplantation. Methods: The clinical data of 332 children who received allogeneic kidney transplantation in the First Affiliated Hospital of Zhengzhou University from January 2014 to March 2022 were retrospectively collected. According to the BKPyV load level, the dynamic change process of lymphocytes at different time points were analyzed. The factors that have potential influence on BKPyV infection were screened by Cox regression analysis, and the receiver operating characteristic curve (ROC) was used to evaluate the sensitivity and specificity of the predictive model of infection. Results: Among the 332 children, there were 215 males and 117 females; the age of transplantation was (12.2±3.9) years old; 37 cases were preschool (1-5 years old), and 295 cases were post-school age (6-18 years old). BKPyV load in 224 urine samples and 30 blood samples of children were detected. There were 9 cases of BKPyV-associated viruria and 3 cases of BKPyV associated viremia in pre-school children, 76 cases BKPyV associated viruria and 14 cases of BKPyV associated viremia in post-school children. Multivariate Cox regression analysis showed that higher body mass index (BMI) (HR=1.105, 95%CI: 1.020-1.197), antithyroglobulin (ATG) application (HR=2.196, 95%CI: 1.335-3.613), and higher tacrolimus concentration (HR=2.484, 95%CI: 1.298-4.753), higher natural killer (NK) lymphocyte count (HR=1.193, 95%CI: 1.009-1.411), higher CD14++CD16-cell count (HR=1.096, 95%CI: 1.024-1.173) were independent risk factors for BKPyV associated viruria in post-school children. Delayed graft function (DGF) (HR=4.993, 95%CI: 1.555-16.038), Acute rejection (AR) (HR=6.021, 95%CI: 1.930-18.787), higher CD14++CD16-cell count (HR=1.227, 95%CI: 1.081-1.392) were independent risk factors for BKPyV associated viremia in post-school children. The results of ROC curve analysis showed that combined BMI, immune induction drugs, tacrolimus concentration, NK cell count, and CD14++CD16-cell count predicted the occurrence of BKPyV associated viruria in post-school children after kidney transplantation at 0.5, 1, 2, and 5 years with area under curve (AUC) of 0.712 (95%CI: 0.626-0.798), 0.708 (95%CI: 0.612-0.804), 0.754 (95%CI: 0.668-0.840) and 0.767 (95%CI: 0.685-0.849). The sensitivity and specificity of the model were 64.9%, 61.4%, 61.6%, 55.8% and 70.9%, 72.4%, 76.0%, 84.0%, respectively. Combined with DGF, AR, and CD14++CD16-cell counts predicted the occurrence of BKPyV-associated viremia at 0.5, 1, 2, and 5 years after renal transplantation in post-school children with AUC of 0.791 (95%CI: 0.631-0.951), 0.744 (95%CI: 0.547-0.936), 0.786 (95%CI: 0.629-0.946) and 0.812 (95%CI: 0.672-0.948). The sensitivity and specificity of the model were 76.1%, 67.1%, 75.0%, 77.9% and 88.9%, 89.0%, 89.9%, 88.0%, respectively. Conclusions: The postoperative CD14++CD16-cell level can be used as an independent predictor of BKPyV infection in post-school children after renal transplantation. Combined BMI, immune induction drugs, tacrolimus concentration, NK cell count, CD14++CD16-cell count and combined DGF, AR, CD14++CD16-cell count show good fitting effect in predicting the occurrence of BKPyV-associated viruria and viremia after transplantation in post-school children respectively.
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Vírus BK , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Masculino , Feminino , Humanos , Pré-Escolar , Criança , Adolescente , Lactente , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Tacrolimo , Viremia/etiologia , Infecções por Polyomavirus/epidemiologia , Infecções Tumorais por Vírus/epidemiologiaRESUMO
Objective: To explore the trend and influencing factors of serum lipoprotein (a) (Lp(a)) concentration over time in Chinese community populations. Methods: This study is a prospective cohort study. The participants were enrolled from Chinese Multi-provincial Cohort Study- Beijing projects, completed the cardiovascular disease risk factor surveys in 2002 and 2007, and the serum Lp (a) concentration were measured. Based on the Lp(a) concentration at baseline (2002) and follow-up (2007), the participants were classified into subgroups of <30.0 mg/dl (1 mg/dl=0.01 g/L) group, 30.0 to 49.9 mg/dl group, and ≥50.0 mg/dl group, respectively. Multivariable logistic regression analysis was used to identify influencing factors associated with Lp (a) absolute change (≥20 mg/dl) and relative change (≥20%) within 5 years. Results: Among 1 955 participants with age of (56.5±8.0) years old and 821 male (42.0%) at baseline, there were 1 657 (84.8%), 184 (9.4%) and 114 (5.8%) participants in Lp(a)<30.0 mg/dl group, 30.0 to 49.9 mg/dl group and ≥50.0 mg/dl group, respectively. Among the baseline Lp(a) concentration of 30.0-49.9 mg/dl group, 68 (37.0%) participants progressed to Lp(a) ≥50.0 mg/dl after 5 years follow-up, and 102 (55.4%) remained at this level. Participants with baseline Lp(a)<30.0 mg/dl (92%, 1 524/1 657) or Lp(a)≥50.0 mg/dl (94.7%, 108/114) tended to be maintained at their respective levels. The results of the multivariate logistic regression analysis showed that, in addition to the high level of baseline Lp(a) concentration, family history of cardiovascular disease, elevated fasting blood glucose and usage of oral lipid-lowering drugs were the influencing factors of Lp(a) changes over time (P<0.05). Conclusions: Adults with borderline-high Lp(a) concentrations (30.0 to 49.9 mg/dl) could be considered for repeated testing, especially for those with a family history of cardiovascular disease, elevated fasting blood glucose and usage of statins.
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Doenças Cardiovasculares , Lipoproteína(a) , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia , Estudos de Coortes , Estudos Prospectivos , Biomarcadores , Fatores de RiscoRESUMO
Objective: To compare the 5-year follow-up outcomes of radiofrequency catheter ablation (RFCA) combined with left atrial appendage closure (LAAC) and long-term oral anticoagulant (OAC) after RFCA in patients with atrial fibrillation. Methods: This retrospective cross-sectional study included patients with atrial fibrillation who underwent"one-stop"procedure in the First Affiliated Hospital of Ningbo University from September 2015 to December 2017 (RFCA+LAAC group). Baseline data of patients were collected. Propensity score matching at the ratio of 1â¶1 was used to select patients with atrial fibrillation who took long-term OAC after RFCA (RFCA+OAC group). The maintenance rate of sinus rhythm and the incidence of adverse events during follow-up were compared between the two groups. Results: A total of 110 patients were enrolled in the RFCA+LAAC group and RFCA+OAC group, respectively. Age of patients was (67.4±8.8) years in RFCA+LAAC group, and there were 42 (38.2%) female patients. Age of patients was (67.3±7.9) years in RFCA+OAC group, and there were 47 (42.7%) female patients. The patients were followed up for mean of (5.3±1.1) years. There was no significant difference in the maintenance rate of sinus rhythm (log-rank: χ2=0.277, P=0.602) and incidence of ischemic stroke events (2.7% (3/110) vs. 4.5% (5/110), P=0.719) during follow-up between the two groups. The incidence of bleeding events (6.4% (7/110) vs. 18.2% (20/110), P=0.008) and major bleeding events (1.8% (2/110) vs. 8.2% (9/110), P=0.030) was significantly higher in the RFCA+OAC group than in the RFCA+LAAC group. Conclusion: There is no significant difference between RFCA+LAAC group and RFCA+OAC group in maintenance rate of sinus rhythm and incidence of ischemic stroke events. Patients in the RFCA+LAAC group have a lower risk of bleeding events compared to the RFCA+OAC group.
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Fibrilação Atrial , Ablação por Cateter , AVC Isquêmico , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Fibrilação Atrial/cirurgia , Estudos Transversais , Seguimentos , Estudos Retrospectivos , Anticoagulantes/uso terapêuticoRESUMO
The small intestine is the primary site of nutrient digestion and absorption, which plays a key role in the survival of neonatal calves. A comprehensive assessment of the phosphoproteomic changes in the small intestine of neonatal calves is unavailable; therefore, we used phosphopeptide enrichment coupled with liquid chromatography-tandem mass spectrometry to investigate the changes in the phosphoproteome profile in the bovine small intestine during the first 36 h of life. Twelve neonatal male calves were assigned to one of the following groups: (1) calves not fed colostrum and slaughtered approximately 2 h postpartum (n = 3), (2) calves fed colostrum at 1 to 2 h and slaughtered 8 h postpartum (n = 3), (3) calves fed 2 colostrum meals (at 1-2 and 10-12 h) and slaughtered 24 h postpartum (n = 3), (4) calves fed 3 colostrum meals (at 1-2, 10-12, and 22-24 h) and slaughtered 36 h postpartum (n = 3). Mid-duodenal, jejunal, and ileal samples of the calves were collected after slaughter. We identified 1,678 phosphoproteins with approximately 3,080 phosphosites, which were mainly Ser (89.9%), Thr (9.8%), and Tyr (0.3%) residues; they belonged to the prodirected (52.9%), basic (20.4%), acidic (16.6%), and Tyr-directed (1.7%) motif categories. The regional differentially expressed phosphoproteins included zonula occludens 2, sorting nexin 12, and protein kinase C, which are mainly associated with developmental processes, intracellular transport, vesicle-mediated transport, and immune system process. They are enriched in the endocytosis, tight junction, insulin signaling, and focal adhesion pathways. The temporal differentially expressed phosphoproteins included occludin, epsin 1, and bridging integrator 1, which were mainly associated with macromolecule metabolic process, cell adhesion, and growth. They were enriched in the spliceosomes, adherens junctions, and tight junctions. The observed changes in the phosphoproteins in the tissues of small intestine suggest the protein phosphorylation plays an important role in nutrient transport and immune response of calves during early life, which needs to be confirmed in a larger study.
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Insulinas , Fosfoproteínas , Gravidez , Feminino , Bovinos , Animais , Masculino , Animais Recém-Nascidos , Fosfoproteínas/análise , Fosfoproteínas/metabolismo , Ocludina/análise , Ocludina/metabolismo , Fosfopeptídeos/análise , Fosfopeptídeos/metabolismo , Nexinas de Classificação/análise , Nexinas de Classificação/metabolismo , Colostro/química , Intestino Delgado/metabolismo , Proteína Quinase C/análise , Proteína Quinase C/metabolismoRESUMO
Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Marketing , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Estados Unidos , United States Food and Drug AdministrationRESUMO
OBJECTIVE: To explore whether the using of mimetic peptide Gap27, a selective inhibitor of connexin 43 (Cx43), could block the death of dopamine neurons and influence the expression of Cx43 in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease mouse models. METHODS: Eighteen C57BL/6 mice were randomly divided into control group, 6-OHDA group and 6-OHDA+Gap27 group, with 6 mice in each group. Bilateral substantia nigra stereotactic injection was performed. The control group was injected with ascorbate solution, 6-OHDA group was injected with 6-OHDA solution, and 6-OHDA+Gap27 group was injected with 6-OHDA and Gap27 mixed solution. Immuno-histochemical staining was used to detect the number of dopamine neurons, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of Cx43 messenger ribonucleic acid (mRNA), immuno-fluorescence staining was used to detect the distribution of Cx43 protein, the contents of Cx43 protein and Cx43 phosphorylation at serine 368 (Cx43-ps368) in mouse midbrain were detected by Western blot. RESULTS: After injection of 6-OHDA, numerous dopamine neurons in substantia nigra died as Cx43 content increased, Cx43-ps368 content decreased. Mixing Gap27 while injecting 6-OHDA could reduce the number of death dopamine neurons and weaken the changes of Cx43 and Cx43-ps368 content caused by 6-OHDA. The number of tyrosine hydroxylase (TH) immunoreactive positive neurons in 6-OHDA group decreased to 27.7% ± 0.02% of the control group (P < 0.01); The number of TH immunoreactive positive neurons in 6-OHDA+Gap27 group was (1.64±0.16) times higher than that in 6-OHDA group (P < 0.05); The content of total Cx43 protein in 6-OHDA group was (1.44±0.07) times higher than that in 6-OHDA+Gap27 group (P < 0.05) while (1.68±0.07) times higher than that in control group (P < 0.01). In 6-OHDA group, the content of Cx43-ps368 protein and its proportion in total Cx43 protein were significantly lower than that in 6-OHDA+Gap27 group (P < 0.05). CONCLUSION: In 6-OHDA mouse models, mimetic peptide Gap27 played a protective role in reducing the damage to substantia nigra dopamine neurons, which was induced by 6-OHDA. The overexpression of Cx43 protein might have neurotoxicity to dopamine neuron. Meanwhile, decreasing Cx43 protein level and keeping Cx43-ps368 protein level may be the protective mechanisms of Gap27.
Assuntos
Doença de Parkinson , Animais , Conexina 43/genética , Conexina 43/metabolismo , Conexina 43/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina/efeitos adversos , Oxidopamina/metabolismo , Doença de Parkinson/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/farmacologiaRESUMO
Objective: To explore the long-term efficacy of low-dose rituximab (RTX) treatment in patients with primary membranous nephropathy (PMN). Methods: Patients with biopsy-proven PMN who received low-dose RTX as initial or second-line regimen from August 2018 to May 2020 in the Department of Nephrology, Tianjin Medical University General Hospital were respectively enrolled. The clinical parameters of patients were urinary protein>3.5 g/24 h, serum albumin<30 g/L and estimated glomerular filtration rate (eGFR)>20 ml·min-1·(1.73 m2)-1. The treatment response of patients with PMN was observed during follow-up, and the remission rate of patients with urinary protein<8 g/24 h or ≥8 g/24 h, anti-PLA2R antibody<150 RU/ml or ≥150 RU/ml, eGFR≥ 60 ml·min-1·(1.73 m2)-1 or<60 ml·min-1·(1.73 m2)-1 were analyzed, respectively. Results: A total of 40 patients were enrolled, including 26 males and 14 females, aged (53±15) years. There were 14 patients received RTX as initial treatment and 26 patients as second-line therapy. The total median dose of RTX in the first course was 800 (425, 1 075) mg. The overall remission rate at the 1st, 3rd, 6th, 12th and 24th months were 12.5% (5/40), 17.5% (7/40), 47.5% (19/40), 57.5% (23/40), 60% (24/40), respectively. The median overall response time was 6.0 (3.0, 7.5) months. Two cases relapsed. Patients with remission (n=24) had a higher level of baseline eGFR [(93.9±28.0) vs (62.4±28.1) ml·min-1·(1.73 m2)-1, P=0.001), and a lower level of both urinary protein [5.9 (5.0, 6.5) vs 11.7 (8.6, 15.5) g/24 h, P<0.001] and anti-PLA2R antibody level [73 (29, 132) vs 453 (182, 950) RU/ml, P=0.004] than those without remission (n=16) 24 month after treatment. There was no statistically significant difference in the remission rate between initial and second-line treatment (P=0.101). Moreover, patients had a higher remission rate in urinary protein<8 g/24 h group (21/26 vs 3/14, P<0.001), anti-PLA2R antibody<150 RU/ml group (16/19 vs 5/16, P=0.002) and eGFR ≥ 60 ml·min-1·(1.73 m2)-1 group (22/29 vs 2/11, P=0.003). Conclusions: Low-dose RTX treatment in PMN is effective during long-term follow-up, and has a lower recurrence rate. The results also suggest that it is more suitable for patients with baseline urinary protein<8 g/24 h, anti-PLA2R antibody<150 RU/ml and eGFR≥ 60 ml·min-1·(1.73 m2)-1.
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Glomerulonefrite Membranosa , Feminino , Humanos , Masculino , Autoanticorpos , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/metabolismo , Imunossupressores/uso terapêutico , Receptores da Fosfolipase A2 , Rituximab/uso terapêutico , Albumina Sérica/uso terapêutico , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
Objective: To analyze the survival and prognosis of Hodgkin lymphoma (HL) patients receiving standard first-line therapy. Methods: Data of clinical characteristics and treatment outcomes of patients with HL diagnosed in Cancer Hospital Chinese Academy of Medical Sciences (CHCAMS) from January 1st, 2000 to December 31st, 2018 who received standard first-line treatment were retrospectively analyzed and compared with that of HL patients who received treatment in the Surveillance, Epidemiology and End Results (SEER) database in the United States during the same period. Factors associated with freedom from progression (FFP) of patients in CHCAMS were analyzed. Treatment and survival data of patients with relapsed/refractory HL (r/rHL) who had failed the standard first-line treatment during the corresponding period in CHCAMS were collected to analyze the outcomes of salvage therapy. Results: A total of 764 HL patients in CHCAMS were included in this study. The median age was 30 years (range, 14-83 years), with 424 males and 340 females. By February 26th, 2022, the patients were followed-up for a median time of 111 months(range, 0.3-262.0 months). Lymphoma-specific survival (LSS) rate and overall survival (OS) rate at 10 years for HL patients in CHCAMS was 91.7% (95%CI: 89.5%-93.9%) and 87.1% (95%CI: 84.5%-89.8%), respectively. LSS and OS rate at 10 years for HL patients from SEER database was 86.8% (95%CI: 86.3%-87.2%) and 79.0% (95%CI: 78.5%-79.5%), respectively. The unadjusted LSS and OS rate for patients in CHCAMS were higher than those for patients from SEER database (both P<0.001). No significant difference was observed in LSS and OS rate (both P>0.05) between the two groups after adjustment. European Organization for Research and Treatment of Cancer staging system (early-stage unfavorable: HR=2.35, 95%CI: 1.13-4.89, P=0.023; advanced stage: HR=5.44, 95%CI: 2.62-11.30, P<0.001) and serum ß2 microglobulin (HR=1.67, 95%CI: 1.08-2.58, P=0.021) were influencing factors of FFP for patients in CHCAMS. The complete remission rate, median progression-free survival (PFS), 5-year PFS rate and 5-year OS rate for the 116 patients with r/rHL was 37.9% (95%CI: 29.6%-47.0%), 15.0 months (95%CI: 9.9-20.1 months), 29.9% (95%CI: 20.9%-38.9%) and 62.9% (95%CI: 54.1%-71.7%), respectively. Conclusions: The outcomes of HL patients receiving standard first-line treatment are excellent. However, the therapeutic effect of HL patients who incurrs disease progression or relapse after standard first-line treatment is not satisfying.
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Doença de Hodgkin , Feminino , Masculino , Humanos , Adulto , Estudos Retrospectivos , Prognóstico , Terapia de Salvação , Bases de Dados FactuaisRESUMO
Phase modulators based upon the thermo-optic effect are used widely in silicon photonics for low speed applications such as switching and tuning. The dissipation of the heat produced to drive the device to the surrounding silicon is a concern as it can dictate how compact and tightly packed components can be without concerns over thermal crosstalk. In this paper we study through modelling and experiment, on various silicon on insulator photonic platforms, how close waveguides can be placed together without significant thermal crosstalk from adjacent devices.
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The aim of this study was to investigate the effect of erythropoietin (EPO) on the apoptosis of retinal ganglion cells (RGCs) induced by high glucose and its mechanism. Rat primary RGCs were extracted to establish high glucose-induced apoptosis models using a 30 mM high-glucose medium. Then flow cytometry, cell counting kit-8 (CCK-8) assay and Western blotting assay were performed to detect the effects of high-, medium- and low-dose EPO on the apoptosis of RGCs induced by high glucose. Next, the molecular mechanism by which EPO suppressed the high glucose-induced apoptosis of RGCs was explored via gene array assay and bioinformatics analysis. The results and mechanism of bioinformatics analysis were verified by Western blotting assay. Finally, the small interfering ribonucleic acid (siRNA) experiment was applied to knock down tyrosine-protein phosphatase non-receptor type 1 (PTPN1) and PTPN11 to verify their roles in the inhibition of EPO on the apoptosis of RGCs triggered by high glucose. Flow cytometry-Annexin V/propidium iodide (PI) staining and CCK-8 assay confirmed that the high-, medium- and low-dose EPO inhibited the apoptosis of RGCs induced by high glucose in a dose-dependent manner (P<0.05). Subsequently, Western blotting assay results manifested that the high-, medium- and low-dose EPO reduced the expression levels of apoptosis-related proteins active-cysteinyl aspartate specific proteinase 3 (Caspase 3) and active- Caspase 9 in a dose-dependent manner (P<0.05). Moreover, according to gene array assay and bioinformatics analysis results, the c-Jun N-terminal kinase (JNK) signaling pathway, PTPN1 and PTPN11 might exert crucial effects in the inhibition of EPO on the apoptosis of RGCs induced by high glucose. Western blotting assay results also demonstrated that, compared with the high-glucose treatment, the high-dose EPO treatment decreased the protein expression level of phosphorylated (p)-JNK1/JNK but increased the protein expression levels of PTPN1 and PTPN11 (P<0.05). Moreover, flow cytometry-Annexin V/PI staining and CCK-8 assay results revealed that in EPO-treated cells, knocking down PTPN1 and PTPN11 significantly reversed the protective effect of EPO against high glucose-induced retinal ganglion cell apoptosis (P<0.05). Lastly, Western blotting assay illustrated that knocking down PTPN1 and PTPN11 significantly abolished the inhibition of high-dose EPO on the JNK signaling pathway. EPO may suppress the JNK signaling pathway by raising the expression levels of PTPN1 and PTPN11, so as to inhibit the apoptosis of RGCs triggered by high glucose.
Assuntos
Eritropoetina , Células Ganglionares da Retina , Animais , Apoptose , Eritropoetina/farmacologia , Glucose , Sistema de Sinalização das MAP Quinases , RatosRESUMO
AIM: To review the removal of Y-shaped airway self-expanding covered metallic stents using the interventional technique under fluoroscopy. MATERIALS AND METHODS: The clinical data of 33 patients who underwent removal of Y-shaped airway self-expanding covered metallic stents from March 2011 to August 2019 were analysed retrospectively. RESULTS: A total of 35 Y-shaped stents were removed. The average indwelling duration of the tracheal stents was 101.7 ± 105.4 days. Four cases were removed via the conventional method (grasping the upper tip of the stent to collapse and adduct the proximal end of the stent), whereas 31 cases were removed using the reversal method (grasping the distal end of the stent to invert and strip out the stent). The duration of stent removal was 24.3 ± 12.4 minutes (median time, 20 minutes). CONCLUSION: The interventional radiology technique is a feasible, safe, and effective method for removing Y-shaped airway self-expanding covered metallic stents, and can be considered for use in the clinical setting.