RESUMO
In medical image segmentation, it is often necessary to collect opinions from multiple experts to make the final decision. This clinical routine helps to mitigate individual bias. However, when data is annotated by multiple experts, standard deep learning models are often not applicable. In this paper, we propose a novel neural network framework called Multi-rater Prism (MrPrism) to learn medical image segmentation from multiple labels. Inspired by iterative half-quadratic optimization, MrPrism combines the task of assigning multi-rater confidences and calibrated segmentation in a recurrent manner. During this process, MrPrism learns inter-observer variability while taking into account the image's semantic properties and finally converges to a self-calibrated segmentation result reflecting inter-observer agreement. Specifically, we propose Converging Prism (ConP) and Diverging Prism (DivP) to iteratively process the two tasks. ConP learns calibrated segmentation based on multi-rater confidence maps estimated by DivP, and DivP generates multi-rater confidence maps based on segmentation masks estimated by ConP. Experimental results show that the two tasks can mutually improve each other through this recurrent process. The final converged segmentation result of MrPrism outperforms state-of-the-art (SOTA) methods for a wide range of medical image segmentation tasks. The code is available at https://github.com/WuJunde/MrPrism.
RESUMO
BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC), which is featured by low incidence, high malignancy rate, robust aggressive behavior and inferior prognosis. To date, there is no standardized treatment. The aim of this study is to better understand and accumulate more clinical experience of the disease by summarizing the clinicopathological features, diagnosis methods, therapeutic regimen and prognostic factors of PSC. METHODS: A total of 39 patients with PSC who diagnosed and received treatment in Beijing Chest Hospital from December 2013 to December 2023 were retrospectively recruited, and information including demographic characteristics, clinicopathological features, tumor-node-metastasis (TNM) stage, diagnosis method and therapeutic regimen were carefully collected. Meanwhile, follow-up was conducted. Kaplan-Meier method was used to analyze the prognostic factors of the disease. RESULTS: The PSC patients in this study ranged in age from 45 to 76 years old, including 35 males and 4 females. There were no specific clinical manifestations of PSC at initial diagnosis. Among the 39 patients, 20 underwent surgical resection and 19 received palliative chemoradiation or symptomatic supportive treatment. The 1-year and 5-year survival rates were 61.90% and 35.20% respectively. Univariate analysis indicated that family history of carcinoma, primary tumor site, TNM stage, lymph node metastasis, distant metastasis, whether or not received surgical resection, surgical method, treatment regimens, tumor tissue programmed cell death ligand 1 (PD-L1) expression ≥1% and mesenchymal-epithelial transition factor (MET) pathway abnormalities were correlated with the overall survival (OS) of patients (P<0.05). In the subsequent multivariate analysis, lymph node metastasis emerged as the only independent prognosticator in predicting inferior OS (P=0.037). CONCLUSIONS: PSC is rarely seen in clinical practice and commonly occurs in elder men with smoking history. Tumor tissue PD-L1 expression ≥1% and MET abnormalities may predict inferior prognosis of PSC and lymph node metastasis was determined as the independent prognosticator of PSC. Surgical resection along with adjuvant medical treatment is the cornerstone for early and locally advanced patients, and the clinical utility of molecular targeting therapy and immunotherapy in PSC needs to be further investigated.
Assuntos
Neoplasias Pulmonares , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Prognóstico , Estudos Retrospectivos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Estadiamento de NeoplasiasRESUMO
Adding synthetic nucleotides to DNA increases the linear information density of DNA molecules. Here we report that it also can increase the diversity of their three-dimensional folds. Specifically, an additional nucleotide (dZ, with a 5-nitro-6-aminopyridone nucleobase), placed at twelve sites in a 23-nucleotides-long DNA strand, creates a fairly stable unimolecular structure (that is, the folded Z-motif, or fZ-motif) that melts at 66.5 °C at pH 8.5. Spectroscopic, gel and two-dimensional NMR analyses show that the folded Z-motif is held together by six reverse skinny dZ-:dZ base pairs, analogous to the crystal structure of the free heterocycle. Fluorescence tagging shows that the dZ-:dZ pairs join parallel strands in a four-stranded compact down-up-down-up fold. These have two possible structures: one with intercalated dZ-:dZ base pairs, the second without intercalation. The intercalated structure would resemble the i-motif formed by dC:dC+-reversed pairing at pH ≤ 6.5. This fZ-motif may therefore help DNA form compact structures needed for binding and catalysis.
RESUMO
OBJECTIVE: To investigate the effects of mild SARS-CoV-2 infection on hematological parameters of adult blood donors and the suitability of apheresis platelet donation, the changes of the hematological parameters in blood donors with mild infection of the SARS-CoV-2 Omicron variant strain were evaluated. METHODS: Seventy-two blood donors with mild COVID-19 symptoms who donated consecutive apheresis platelets for 3 times from December 2022 to January 2023, 42 cases among which were included in the infection-positive group, and 30 cases in the suspected infection group. Forty-two donors un-vaccinated against SARS-CoV-2, un-infected, and donated three consecutive apheresis platelets from October to November 2022 were included in the control group. The changes of blood routine testing in the positive group and the suspected infection group were retrospectively compared before (Time1) and after (Time2 and Time3) the onset of symptoms, three consecutive times (Time1, Time2, Time3) in the control group by repeated measures analysis of variance. The Bayesian discriminant method was used to establish a discriminant equation to determine whether the recent infection of SARS-CoV-2 occurred or not. RESULTS: Simple effect of the number times of tests in the positive and suspected infection groups was significantï¼ Finfection-positive group=6.98, P < 0.001, partial η2=0.79, Fsuspected infection group=4.31, P < 0.001, partial η2=0.70ï¼. The positive group and the suspected infection group had lower RBC, HCT, and HGB, and higher PLT and PCT at Time2 compared to Time1 and Time3(P < 0.05). The positive group and the suspected infection group showes RDW-CV and RDW-SD at Time3 higher than Time1 and Time2 (P < 0.001). The simple effect of the number times of tests in the control group was not significant ( F=0.96, P =0.55, partial η2=0.34). The difference of the whole blood count parameters in the control group for three times was not statistically significant (P >0.05). We established a discriminant equation to determine whether the recent infection of SARS-CoV-2 occurred or not. The equation had an eigenvalue of 0.22, a canonical correlation of 0.43 (χ2=27.81, P < 0.001), and an analysis accuracy of 72.9%. CONCLUSION: The hematological indicators of RBC, HCT, HGB, PLT, PCT, RDW-CV and RDW-SD in blood donors who had infected with mild COVID-19 showed dynamic changes. The discriminant equation for whether they are infected recently with COVID-19 has a high accuracy rate.
Assuntos
Doadores de Sangue , COVID-19 , Plaquetoferese , SARS-CoV-2 , Humanos , COVID-19/sangue , Plaquetas , Estudos Retrospectivos , Contagem de Plaquetas , Adulto , MasculinoRESUMO
Aim: Coronary artery lesion (CAL) is a common yet serious complication in children with Kawasaki disease. The aim of the present study was to evaluate the influencing factors of CAL in children with Kawasaki disease, to provide reference for the clinical treatment and care of children with Kawasaki disease. Design: A retrospective cohort study. Methods: Children with Kawasaki disease treated in a tertiary hospital in China between 1 January 2021 and 31 December 2022 were selected. The characteristics and clinical data of children with Kawasaki disease were analyzed. Spearman's correlation analysis was conducted to evaluate the relationship between CAL and the characteristics of children with Kawasaki disease. A logistic regression analysis was used to analyze the influencing factors of CAL in children with Kawasaki disease. Results: In total, 185 children with Kawasaki disease were included; the incidence of CAL in children with Kawasaki disease was 18.38%. Pearson's correlation analysis showed that gender (r = 0.504), age (r = 0.611), duration of fever ≥10 days (r = 0.579), hemoglobin (Hb) (r = 0.623), and C-reactive protein (CRP) (r = 0.558) were all correlated with the CAL in children with Kawasaki disease (all p < 0.05). Logistic regression analyses showed that male [odds ratio (OR) = 2.543, 95% confidence interval (CI): 1.801-3.077, p = 0.040], age ≤2 years (OR = 3.002, 95% CI: 2.744-3.641, p = 0.012), duration of fever ≥10 days (OR = 2.089, 95% CI: 1.624-2.515, p = 0.028), Hb ≤105â g/L (OR = 1.914, 95% CI: 1.431-2.406, p = 0.013), and CRP ≥100â mg/L (OR = 2.168, 95% CI: 1.893-2.531, p = 0.035) were the risk factors of CAL in children with Kawasaki disease (all p < 0.05). Conclusions: The incidence of CAL in children with Kawasaki disease is high and there are many related risk factors. Clinical medical workers should take early warning and carry out interventions and nursing care according to these risk factors to improve the prognosis of children with Kawasaki disease.
RESUMO
PURPOSE: We investigated the relationships among motor function, physical activity, and the characteristics of chronic pain (the number of pain sites, pain intensity, and pain-type). DESIGN: Cross-sectional study. SETTING: An ongoing community-based prospective study conducted in Itoshima, Japan. SUBJECTS: Community-dwelling Japanese aged 65-75 years (n = 805; 401 men, 404 women). MEASURES: Chronic pain subtypes were examined in terms of the number of pain sites, pain intensity, and pain type. Motor function was evaluated by handgrip strength, walking speed, and the 5 Times Stand-up and Sit Test (FTSST). Locomotive activity, non-locomotive activity, and sedentary time were evaluated by a tri-axial accelerometer as physical-activity parameters. ANALYSIS: Multiple regression model adjusting for age, sex, education level, employment status, subjective economic status, body mass index, cognitive function, comorbidity, current tobacco use, current alcohol consumption, and regular exercise. RESULTS: In a multivariate analysis, the subjects' walking speed was negatively associated with multisite, moderate-to-severe, and neuropathic-like pain. The FTSST was positively associated with single-site, moderate-to-severe, and neuropathic-like pain. There was no significant association between handgrip strength and any chronic pain subtypes. Locomotive activity was negatively related to multisite, moderate-to-severe, and neuropathic-like pain, but there was no clear association between the amount of non-locomotive activity, sedentary time, and chronic pain subtypes. CONCLUSION: Severe chronic pain was associated with decreased locomotion-related motor function and physical activity.
RESUMO
With just four building blocks, low sequence information density, few functional groups, poor control over folding, and difficulties in forming compact folds, natural DNA and RNA have been disappointing platforms from which to evolve receptors, ligands, and catalysts. Accordingly, synthetic biology has created "artificially expanded genetic information systems" (AEGIS) to add nucleotides, functionality, and information density. With the expected improvements seen in AegisBodies and AegisZymes, the task for synthetic biologists shifts to developing for expanded DNA the same analytical tools available to natural DNA. Here we report one of these, an enzyme-assisted sequencing of expanded genetic alphabet (ESEGA) method to sequence six-letter AEGIS DNA. We show how ESEGA analyses this DNA at single base resolution, and applies it to optimized conditions for six-nucleotide PCR, assessing the fidelity of various DNA polymerases, and extending this to AEGIS components with functional groups. This supports the renewed exploitation of expanded DNA alphabets in biotechnology.
Assuntos
DNA , Sequenciamento de Nucleotídeos em Larga Escala , Sequenciamento de Nucleotídeos em Larga Escala/métodos , DNA/genética , DNA/metabolismo , Biologia Sintética/métodos , DNA Polimerase Dirigida por DNA/metabolismo , DNA Polimerase Dirigida por DNA/genética , Reação em Cadeia da Polimerase/métodos , Sequência de Bases , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND: To determine the predictive value of interstitial lung abnormalities (ILA) for epidermal growth factor receptor (EGFR) mutation status and assess the prognostic significance of EGFR and ILA in patients with non-small cell lung cancer (NSCLC). METHODS: We reviewed 797 consecutive patients with a histologically proven diagnosis of primary NSCLC from January 2013 to October 2018. Of these, 109 patients with NSCLC were found to have concomitant ILA. Multivariate logistic regression analysis was used to identify the significant clinical and computed tomography (CT) findings in predicting EGFR mutations. Cox proportional hazard models were used to identify significant prognostic factors. RESULTS: EGFR mutations were identified in 22 of 109 tumors (20.2%). Multivariate analysis showed that the models incorporating clinical, tumor CT and ILA CT features yielded areas under the receiver operating characteristic curve (AUC) values of 0.749, 0.838, and 0.849, respectively. When combining the three models, the independent predictive factors for EGFR mutations were non-fibrotic ILA, female sex, and small tumor size, with an AUC value of 0.920 (95% confidence interval[CI]: 0.861-0.978, p < 0.001). In the multivariate Cox model, EGFR mutations (hazard ratio = 0.169, 95% CI = 0.042-0.675, p = 0.012; 692 days vs. 301 days) were independently associated with extended overall survival compared to the wild-type. CONCLUSION: Non-fibrotic ILA independently predicts the presence of EGFR mutations, and the presence of EGFR mutations rather than non-fibrotic ILA serves as an independent good prognostic factor for patients with NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Mutação , Tomografia Computadorizada por Raios X , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Feminino , Masculino , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Idoso , Prognóstico , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Valor Preditivo dos Testes , Adulto , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: The vestibular aqueduct (VA) serves an essential role in homeostasis of the inner ear and pathogenesis of Ménière's disease (MD). The bony VA can be clearly depicted by high-resolution computed tomography (HRCT), whereas the optimal sequences and parameters for magnetic resonance imaging (MRI) are not yet established. We investigated VA characteristics and potential factors influencing MRI-VA visibility in unilateral MD patients. METHODS: One hundred patients with unilateral MD underwent MRI with three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) sequence and HRCT evaluation. The imaging variables included MRI-VA and CT-VA visibility, CT-VA morphology and CT-peri-VA pneumatization. RESULTS: The most frequent type of MRI-VA and CT-VA visualization was invisible VA and continuous VA, respectively. The MRI-VA visibility was significantly lower than CT-VA visibility. MRI-VA visibility had a weak positive correlation with ipsilateral CT-VA visualization. For the affected side, the MRI-VA visualization was negatively correlated with the incidence of obliterated-shaped CT-VA and positively with that of tubular-shaped CT-VA. MRI-VA visualization was not affected by CT-peri-VA pneumatization. CONCLUSION: In patients with MD, the VA visualization on 3D-SPACE MRI is poorer than that observed on CT and may be affected by its osseous configuration. These findings may provide a basis for further characterization of VA demonstrated by MRI and its clinical significance.
Assuntos
Imageamento por Ressonância Magnética , Doença de Meniere , Tomografia Computadorizada por Raios X , Aqueduto Vestibular , Humanos , Doença de Meniere/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Aqueduto Vestibular/diagnóstico por imagem , Feminino , Masculino , Tomografia Computadorizada por Raios X/métodos , Pessoa de Meia-Idade , Adulto , Idoso , Imageamento Tridimensional/métodos , Adulto JovemRESUMO
CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases , Receptores de Fator Estimulador de Colônias/antagonistas & inibidores , Receptores de Fator Estimulador de Colônias/metabolismo , Piridonas/farmacologia , Pirimidinas/farmacologiaRESUMO
Bacterial cellulose (BC) produced by Acetobacter xylinum has great advantages in wound dressing. However, the structural limitation under static culture, and lack of antibacterial properties restrict its application, especially for infectious wound healing. The present study reported an original wound dressing, which was composed of a Janus BC membrane with antibacterial nano-sized copper oxide (CuO) through polydopamine (PDA) conjugation to promote wound healing under infectious condition. The finished product (CuO/PDA/BC membrane) exhibited favorable air permeability, high hydrophilicity and good mechanical properties, as well as strong antibacterial effects by the sustained release of CuO and photothermal effect of CuO/PDA. Furthermore, CuO/PDA/BC membrane inhibited inflammatory response and promoted wound healing in an infectious wound model in vivo. These results suggested that our CuO/PDA/BC membrane had great potential as wound dressing for infectious wound healing.
Assuntos
Celulose , Indóis , Polímeros , Infecção dos Ferimentos , Humanos , Celulose/farmacologia , Celulose/química , Cobre/farmacologia , Cobre/química , Cicatrização , Antibacterianos/farmacologia , Antibacterianos/química , Óxidos/farmacologiaRESUMO
Chronic overlapping pain conditions (COPCs) by definition, frequently co-occur, perhaps reflecting their shared etiologies. Their overlapping nature presents a methodological challenge, possibly masking associations between COPCs and health outcomes attributable to either general or specific processes. To address this challenge, we used population-based cohort data to evaluate the predictive validity of a bifactor model of 9 self-reported COPCs by assessing its association with incident pain-related clinical diagnoses; pain-relevant pharmacotherapy; and other health outcomes. We obtained data from a 2005 to 2006 study of Swedish adult twins linked with health data from nationwide registers through 2016 (N = 25,418). We then fit a bifactor model comprising a general COPC factor and 2 independent specific factors measuring pain-related somatic symptoms and neck and shoulder pain. Accounting for age, biological sex, and cancer, the general factor was associated with increased risk of all pain-related outcomes (eg, COPC diagnosis adjusted odds ratio [aOR], 1.71; 95% confidence interval [1.62, 1.81]), most mental health-related outcomes (eg, depression aOR, 1.72 [1.60, 1.85]), and overdose and mortality (eg, all-cause mortality aOR, 1.25 [1.09, 1.43]). The somatic symptoms specific factor was associated with pain-relevant pharmacotherapy (eg, prescribed opioids aOR, 1.25 [1.15, 1.36]), most mental health-related outcomes (eg, depression aOR, 1.95 [1.70, 2.23]), and overdose (eg, nonfatal overdose aOR, 1.66 [1.31, 2.10]). The neck and shoulder pain-specific factor was weakly and inconsistently associated with the outcomes. Findings provide initial support for the validity and utility of a general-factor model of COPCs as a tool to strengthen understanding of co-occurrence, etiology, and consequences of chronic pain. PERSPECTIVE: This article presents associations between a novel measurement model of COPCs and various health outcomes. Findings provide support for measuring pain across multiple domains rather than only measuring pain specific to one physical location in both research and clinical contexts.
Assuntos
Dor Crônica , Humanos , Masculino , Dor Crônica/diagnóstico , Dor Crônica/epidemiologia , Feminino , Adulto , Pessoa de Meia-Idade , Suécia/epidemiologia , Idoso , Sistema de Registros , Comorbidade , Estudos de Coortes , Adulto JovemRESUMO
OBJECTIVE: Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability to psychopathology or confounded by unmeasured familial factors. The authors investigated the association between psychiatric conditions in young adulthood and the risk of cardiometabolic complications in middle adulthood, up to 40 years later. METHODS: This cohort study (N=672,823) identified all individuals and their siblings born in Sweden between 1955 and 1962 and followed the cohort through 2013. Logistic regression models were used to estimate the bivariate associations between 10 psychiatric conditions or criminal convictions and five cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the comorbidity among psychiatric conditions and criminal convictions. The cardiometabolic complications were then regressed on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs. RESULTS: Each psychiatric condition significantly increased the risk of cardiometabolic complications. These associations appeared nonspecific, as multivariate models indicated that most were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals' general psychopathology and their siblings' cardiometabolic complications. The same pattern was evident for the specific internalizing and psychotic factors. CONCLUSIONS: Associations between mental disorders in early life and later long-term risk of cardiometabolic complications appeared to be attributable to a general liability to psychopathology. Familial coaggregation analyses suggested that the elevated risk could not be attributed to confounders shared within families. One possibility is that lifestyle-based interventions may reduce the risk of later cardiometabolic complications for patients with several mental disorders.
Assuntos
Transtornos Mentais , Humanos , Suécia/epidemiologia , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Masculino , Feminino , Adulto , Estudos Longitudinais , Pessoa de Meia-Idade , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/epidemiologia , Adulto Jovem , Irmãos/psicologia , Comorbidade , Fatores de RiscoRESUMO
Foot-and-mouth disease virus (FMDV) is a highly contagious pathogen that has caused significant economic losses in the livestock industry. Peptide vaccines engineered with the protective epitopes of FMDV have provided a safer alternative for disease prevention than the traditional inactivated vaccines. However, the immunogenicity of the peptide is usually poor and therefore an adjuvant is required. Here, we showed that recombinant T4 phages displaying the B-cell epitope of the FMDV VP1 protein (VP1130-158), without additional adjuvants, induced similar levels of antigen-specific IgG1 but higher levels of IgG2a compared to the peptide vaccine. Incorporation of a CD4+ T cell epitope, either 3A21-35 of FMDV 3A protein or P2830-844 of tetanus toxoid, further enhanced the immunogenicity of VP1-T4 phage nanoparticles. Interestingly, the extrinsic adjuvant cannot enhance the immunogenicity of the nanoparticles, indicating the intrinsic adjuvant activities of T4 phage. Furthermore, the recombinant T4 phage can be produced on a large scale within a short period of time at a relatively low-cost using Escherichia coli, heralding its potential in the development of a safe and effective FMDV vaccine.
Assuntos
Vírus da Febre Aftosa , Febre Aftosa , Vacinas Virais , Animais , Bacteriófago T4 , Febre Aftosa/prevenção & controle , Nanovacinas , Anticorpos Antivirais , Epitopos de Linfócito B , Adjuvantes Imunológicos , Proteínas do CapsídeoRESUMO
Background: Emerging infectious diseases pose a significant threat to both human and animal populations. Rapid de novo identification of protective antigens from a clinical isolate and development of an antigen-matched vaccine is a golden strategy to prevent the spread of emerging novel pathogens. Methods: Here, we focused on Actinobacillus pleuropneumoniae, which poses a serious threat to the pig industry, and developed a general workflow by integrating proteosurfaceomics, secretomics, and BacScan technologies for the rapid de novo identification of bacterial protective proteins from a clinical isolate. Results: As a proof of concept, we identified 3 novel protective proteins of A. pleuropneumoniae. Using the protective protein HBS1_14 and toxin proteins, we have developed a promising multivalent subunit vaccine against A. pleuropneumoniae. Discussion: We believe that our strategy can be applied to any bacterial pathogen and has the potential to significantly accelerate the development of antigen-matched vaccines to prevent the spread of an emerging novel bacterial pathogen.
Assuntos
Actinobacillus pleuropneumoniae , Pleuropneumonia , Animais , Humanos , Suínos , Antígenos de Bactérias , Vacinas Bacterianas , Proteínas de Bactérias , Pleuropneumonia/microbiologia , Pleuropneumonia/prevenção & controleRESUMO
BACKGROUND The aim of this study was to analyze the correlation and the accuracy of lower-extremity torsion deformities measured by physical examination, CT scan, and three-dimensional gait analysis in children with CP. MATERIAL AND METHODS The study group included 72 children with CP with lower-extremity torsion deformities. All subjects were assessed by: 1. physical examination: maximum internal rotation (MIR), maximum external rotation (MER) for hip joint torsion, and transmalleolar axis (TMA) for tibial torsion; 2. CT scanning: femoral anteversion (FAV) and tibial torsion (TT); 3. three-dimensional gait analysis kinematic parameters: single-support phase of femoral rotation, double-support phase of femoral rotation, swing phase of femoral rotation and single-support phase of tibial rotation, double-support phase of tibial rotation, and swing phase of tibial rotation. Statistical analysis was performed using the Pearson correlation test. A significance level of P<0.05 was set. RESULTS In femurs, MIR and MER were correlated with FAV, and the correlation of MER was higher, while physical examination and FAV were not correlated with any kinematic data in gait analysis. In tibias, there was no correlation between TMA and TT, but both TMA and TT were correlated with the gait analysis kinematic data, and the correlation of TT was higher. TMA was more correlated with tibial rotation during swing phase, while TT was more correlated with tibial rotation in single-support phase. CONCLUSIONS Three-dimensional gait analysis can analyze the tibial rotation of children with cerebral palsy, which is highly correlated with CT and physical examination. However, femoral rotation was not associated with CT and physical examination.
Assuntos
Paralisia Cerebral , Análise da Marcha , Criança , Humanos , Paralisia Cerebral/diagnóstico por imagem , Exame Físico , Tomografia Computadorizada por Raios X , Extremidade Inferior/diagnóstico por imagemRESUMO
INTRODUCTION: Depressive symptoms have surfaced as the principal mental health concern among patients with breast cancer, with surgical interventions potentially exacerbating these symptoms and adversely influencing clinical outcomes. This study protocol is designed to investigate the efficacy of low-dose esketamine administered perioperatively on depressive symptoms in patients with breast cancer. It also aims to illuminate the potential neurobiological underpinnings of this effect. METHODS AND ANALYSIS: This research represents a single-centre, prospective, randomised, double-blind, placebo-controlled study. The trial anticipates enrolling 108 female patients exhibiting mild-to-severe depressive symptoms who are slated for radical mastectomy. Through stratified randomisation, eligible patients will be systematically assigned to either the esketamine group (0.25 mg/kg) or placebo group (0.9% saline) in a 1:1 ratio. The primary outcome is the response rate at the third postoperative day. Secondary outcomes encompass the remission rate, depression-related scores, depression severity and safety-related endpoints. Tertiary (exploratory) outcomes involve alterations in brain-derived neurotrophic factor and resting-state functional brain connectivity. ETHICS AND DISSEMINATION: The Clinical Trial Ethics Committee at The First Affiliated Hospital of Anhui Medical University has conferred ethical approvals for this trial (approval number: PJ2023-05-25). Results from this trial will be disseminated in peer-reviewed journals and presented at professional symposiums. TRIAL REGISTRATION NUMBER: Chinese Clinical Trials Registry (ChiCTR2300071062).
Assuntos
Neoplasias da Mama , Depressão , Humanos , Feminino , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/diagnóstico , Neoplasias da Mama/cirurgia , Estudos Prospectivos , Resultado do Tratamento , Mastectomia/efeitos adversos , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Vaccines that trigger mucosal immune responses at the entry portals of pathogens are highly desired. Here, we showed that antigen-decorated nanoparticle generated through CRISPR engineering of T4 bacteriophage can serve as a universal platform for the rapid development of mucosal vaccines. Insertion of Flu viral M2e into phage T4 genome through fusion to Soc (Small Outer Capsid protein) generated a recombinant phage, and the Soc-M2e proteins self-assembled onto phage capsids to form 3M2e-T4 nanoparticles during propagation of T4 in E. coli. Intranasal administration of 3M2e-T4 nanoparticles maintains antigen persistence in the lungs, resulting in increased uptake and presentation by antigen-presenting cells. M2e-specific secretory IgA, effector (TEM), central (TCM), and tissue-resident memory CD4+ T cells (TRM) were efficiently induced in the local mucosal sites, which mediated protections against divergent influenza viruses. Our studies demonstrated the mechanisms of immune protection following 3M2e-T4 nanoparticles vaccination and provide a versatile T4 platform that can be customized to rapidly develop mucosal vaccines against future emerging epidemics.
Assuntos
Vacinas contra Influenza , Nanopartículas , Infecções por Orthomyxoviridae , Animais , Camundongos , Vacinas contra Influenza/genética , Bacteriófago T4/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Escherichia coli/genética , Infecções por Orthomyxoviridae/prevenção & controle , Camundongos Endogâmicos BALB C , Proteínas da Matriz ViralRESUMO
Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2'-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2'-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO's binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didn't cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oligonucleotides (Se-ASO).