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Biologicals developers often face challenges in accurately determining the extinction coefficient (EC) measurement. We have successfully improved the precision and robustness of the widely recognized amino acid analysis method for EC determination, through a stepwise optimization process. Extensive analyses based on 114 observations, covering eight proteins over three years were performed, with a maximum relative standard deviation of 1.5% among multiple analysts, and a maximum deviation of 2.8% from the theoretical EC across the eight given proteins examined.
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OBJECTIVES: Distant metastasis remains the main cause of death in breast cancer. Breast cancer risk is strongly influenced by pathogenic mutation.This study was designed to develop a multiple-feature model using clinicopathological and imaging characteristics adding pathogenic mutations associated signs to predict recurrence or metastasis in breast cancers in high familial risk women. METHODS: Genetic testing for breast-related gene mutations was performed in 54 patients with breast cancers. Breast MRI findings were retrospectively evaluated in 64 tumors of the 54 patients. The relationship between pathogenic mutation, clinicopathological and radiologic features was examined. The disease recurrence or metastasis were estimated. Multiple logistic regression analyses were performed to identify independent factors of pathogenic mutation and disease recurrence or metastasis. Based on significant factors from the regression models, a multivariate logistic regression was adopted to establish two models for predicting disease recurrence or metastasis in breast cancer using R software. RESULTS: Of the 64 tumors in 54 patients, 17 tumors had pathogenic mutations and 47 tumors had no pathogenic mutations. The clinicopathogenic and imaging features associated with pathogenic mutation included six signs: biologic features (p = 0.000), nuclear grade (p = 0.045), breast density (p = 0.005), MRI lesion type (p = 0.000), internal enhancement pattern (p = 0.004), and spiculated margin (p = 0.049). Necrosis within the tumors was the only feature associated with increased disease recurrence or metastasis (p = 0.006). The developed modelIincluding clinico-pathologic and imaging factors showed good discrimination in predicting disease recurrence or metastasis. Comprehensive model II, which included parts of modelIand pathogenic mutations significantly associated signs, showed significantly more sensitivity and specificity for predicting disease recurrence or metastasis compared to Model I. CONCLUSIONS: The incorporation of pathogenic mutations associated imaging and clinicopathological parameters significantly improved the sensitivity and specificity in predicting disease recurrence or metastasis. The constructed multi-feature fusion model may guide the implementation of prophylactic treatment for breast cancers at high familial risk women.
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Neoplasias da Mama , Predisposição Genética para Doença , Imageamento por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Mutação , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Fenótipo , Estudos Retrospectivos , Metástase Neoplásica/diagnóstico por imagem , Metástase Neoplásica/genética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/secundárioRESUMO
OBJECTIVE: To compare the efficacy of mammography versus ultrasonography in detecting stages T1 and Tis breast cancer. METHODS: Mammography and ultrasonograhpy data were collected for 1 630 stages T1 and Tis breast cancer from July 2011 to July 2013. Chi-square test was used to analyze the detection rate and diagnostic rate of two methods. RESULTS: Among 1 630 patients with 1 665 focus, 1 559 focus were detected by both methods. In term of detection rate, mammography had a higher rate in mostly fatty and scattered fibroglandular breast while ultrasonography offered advantages in extremely dense breast. And statistical significance existed among these groups (P < 0.05). In heterogeneously dense group, the detection rate of two methods had no statistical significance (P > 0.05). In term of diagnostic rate, mammography had a higher diagnostic rate in mostly fatty and scattered fibroglandular breast. On the contrary, ultrasonography was superior to mammography in heterogeneously and extremely dense breast. No statistical significance existed among these groups (P > 0.05). Furthermore the focus were classified into mass and non-mass types based on mammographic images. As the volume of fibroglandular tissue increased, the amount of mass type focus increased while that of non-mass type focus decreased. CONCLUSION: For stages T1 and Tis breast cancer, mammography has higher detection and diagnostic rates in mostly fatty and scattered fibroglandular breast while ultrasonography is better for heterogeneously and extremely dense breast. There are some correlations between fibroglandular and focus types based on mammographic images.
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Neoplasias da Mama , Mamografia , Neoplasias da Mama/diagnóstico por imagem , Humanos , Estadiamento de Neoplasias , UltrassonografiaRESUMO
Background: Mammographic architectural distortion (AD) is usually subtle and has variable presentations and causes, which poses a diagnostic challenge for breast radiologists and consequently a complex decision-making challenge for clinicians and patients. Presently, there is no reliable imaging standard to differentiate between malignant and benign ADs preoperatively. This study aimed to perform a comprehensive analysis of detailed mammographic and ultrasonographic features and clinical characteristics to enhance the diagnostic and differential efficacy for AD lesions. The findings have the potential to boost the diagnostic confidence of breast radiologists when encountering with AD lesions and could be instrumental in refining clinical management strategies for ADs. Methods: This retrospective study included consecutive female patients with ADs on screening or diagnostic mammography from January 6, 2015, to December 28, 2018. The patient's clinical data, mammographic and ultrasonographic or "second look" ultrasonographic findings, and pathological results were reviewed. The continuous variables were analyzed using the t-test. The categorical variables were assessed using the Chi-square test or two-tailed Fisher's exact test. Logistic regression analyses were conducted to evaluate potential risk factors for pathologically proven malignant ADs. Machine learning model based on multimodal clinical and imaging features was constructed using R software. Results: Ultimately, 344 patients with 346 AD lesions were enrolled in the study (mean age: 47.40±10.07 years; range, 19-84 years). Of the ADs, 228 were malignant and 118 were non-malignant. Palpable AD on mammography was more likely to indicate malignancy than non-palpable AD (83.43% vs. 49.15%, P<0.001). AD associated with other mammographic findings was more likely to be malignant than pure AD (73.58% vs. 59.36%, P=0.005). Ultrasonography (US) correlates were observed in 345 of these 346 AD lesions. Among these US correlates, 63 (18.26%, 63/345) were detected by "second look" ultrasound. For the US correlates, the mammographic ADs that appeared as non-mass-like hypoechoic areas and masses on US were more likely to be malignant than those that appeared as other abnormalities (P<0.001). The sensitivity, specificity and diagnostic accuracy of the eXtreme Gradient Boosting (XGBoost) model based on clinical and comprehensive imaging features in differentiation of AD lesions in the validation set were 66.46%, 94.23% and 78.9%, respectively, and the AUC was 0.886 (95% confidence interval: 0.825-0.947). Conclusions: The application of mammograms-guided "second-look" ultrasound could enhance the detection of US correlates, particularly non-mass-like features. The comprehensive analysis based on clinical and multimodal imaging features could be beneficial in improving the diagnostic and differential efficacy for AD lesions detected on mammography and instrumental in refining clinical management strategies for ADs.
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The dynamics of soil arthropod communities in annual monoculture grasslands is still unclear, which restricts the understanding of the degradation mechanism of cultivated grasslands. We cultivated two annual gramineae species, Lolium multiflorum and Avena sativa, separately in Hongyuan County, located on the eastern edge of the Qinghai-Tibet Plateau, in April 2019. We investigated soil arthropods, plant communities and soil properties in the cultivated grasslands and natural grassland in the late September every year from 2019 to 2022. The results showed that: 1) The taxonomic composition of soil arthropod communities differed significantly among three grasslands and sampling years. 2) There was no significant difference in the density, taxonomic richness, Shannon index and evenness index of soil arthropod communities among three grasslands. 3) The density of soil arthropod communities significantly fluctuated across years in three grasslands, and the taxonomic richness and Shannon index decreased significantly in the L. multiflorum and A. sativa grasslands, with the evenness index declining significantly only in the fourth year. The Shannon index fluctuated significantly and the evenness index varied little in natural grassland. 4) The above- and below-ground biomass, the contents of soil total P, total K and available N were the main factors influencing the taxonomic composition, density and diversity indices of soil arthropod communities. The results suggested that the cultivation of annual gramineae grasslands have significant effects on taxonomic composition, but not on density and diversity of soil arthropod communities, and those variables change significantly across different years.
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Artrópodes , Pradaria , Solo , Animais , Artrópodes/classificação , Artrópodes/crescimento & desenvolvimento , Solo/química , China , Biodiversidade , Dinâmica Populacional , Lolium/crescimento & desenvolvimento , Lolium/classificação , Poaceae/crescimento & desenvolvimento , Poaceae/classificação , Avena/crescimento & desenvolvimento , Avena/classificação , AltitudeRESUMO
The aim of this study is to assess the diagnostic performance of contrast-enhanced magnetic resonance (MR) imaging in patients with non-mass-like breast lesions in a meta-analysis. Literature study was performed on PubMed data base on the diagnostic performance of MR imaging in patients with non-mass-like breast lesions. Details of the relevant studies were reviewed and a meta-analysis was performed to estimate the overall sensitivity and specificity of contrast-enhanced MR imaging of non-mass-like breast lesions. A summary receiver operating characteristic curve (sROC) was developed to explore the threshold effect by ROC space. Spearman correlation coefficient was calculated using Meta-Disc version 1.4 to analyze the heterogeneity between studies. A total of 858 non-mass-like lesions from 15 studies were included in the meta-analysis (sample size range: 27-131). Pooled weighted estimates of sensitivity and specificity were 50% (95% CI: 46%, 53%) and 80% (95% CI: 77%, 83%), respectively. The heterogeneity among studies was caused by other factors other than threshold effect. The findings were influenced by cancer prevalence (p = 0.0359). Subgroup analyses indicated that the sensitivity and specificity in studies with combined diagnostic criterion was higher than that in studies with single diagnostic criterion. In evaluation of non-mass-like breast lesions, contrast-enhanced MRI has high specificity and relatively lower sensitivity.
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Mama/patologia , Meios de Contraste , Aumento da Imagem , Imageamento por Ressonância Magnética/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Mepiquat (Mep) is a contaminant produced by Maillard reaction with reducing sugar, free lysine and an alkylating agent under typical roasting conditions, particularly in the range of 200-240 °C. It has been reported that exposure to Mep is harmful to rats. However, its metabolic mechanism is still not clear. In this study, untargeted metabolomics was used to reveal the effect of Mep on the metabolic profile of adipose tissue in Sprague-Dawley rats. Twenty-six differential metabolites were screened out. Eight major perturbed metabolic pathways were found, which were linoleic acid metabolism, Phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, Glycine, serine, and threonine metabolism, glycerolipid metabolism, Alanine, aspartate, and glutamate metabolism, and glyoxylate and dicarboxylic acid metabolism. This study lays a solid foundation for clarifying the toxic mechanism of Mep.
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Background: The nuclear grading of ductal carcinoma in situ (DCIS) affects its clinical risk. The aim of this study was to investigate the possibility of predicting the nuclear grading of DCIS, by magnetic resonance imaging (MRI)-based radiomics features. And to develop a nomogram combining radiomics features and MRI semantic features to explore the potential role of MRI radiomic features in the assessment of DCIS nuclear grading. Methods: A total of 156 patients (159 lesions) with DCIS and DCIS with microinvasive (DCIS-MI) were enrolled in this retrospective study, with 112 lesions included in the training cohort and 47 lesions included in the validation cohort. Radiomics features were extracted from Dynamic contrast-enhanced MRI (DCE-MRI) phases 1st and 5th. After feature selection, radiomics signature was constructed and radiomics score (Rad-score) was calculated. Multivariate analysis was used to identify MRI semantic features that were significantly associated with DCIS nuclear grading and combined with Rad-score to construct a Nomogram. Receiver operating characteristic curves were used to evaluate the predictive performance of Rad-score and Nomogram, and decision curve analysis (DCA) was used to evaluate the clinical utility. Results: In multivariate analyses of MRI semantic features, larger tumor size and heterogeneous enhancement pattern were significantly associated with high-nuclear grade DCIS (HNG DCIS). In the training cohort, Nomogram had an area under curve (AUC) of 0.879 and Rad-score had an AUC of 0.828. Similarly, in the independent validation cohort, Nomogram had an AUC value of 0.828 and Rad-score had an AUC of 0.772. In both the training and validation cohorts, Nomogram had a significantly higher AUC value than Rad-score (P<0.05). DCA confirmed that Nomogram had a higher net clinical benefit. Conclusions: MRI-based radiomic features can be used as potential biomarkers for assessing nuclear grading of DCIS. The nomogram constructed by radiomic features combined with semantic features is feasible in discriminating non-HNG and HNG DCIS.
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RATIONALE AND OBJECTIVES: The study investigated the potential of the combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging in predicting the pathological complete response (pCR) of neoadjuvant chemotherapy (NAC) after two cycles of NAC. MATERIALS AND METHODS: Eighty-seven patients with breast cancer who underwent MR examination before and after two cycles of NAC were enrolled. The patients were randomly assigned to a training cohort and a validation cohort (3:1 ratio). MRI parameters including tumor longest diameter, time-signal intensity curve, early enhanced ratio (E90), maximal enhanced ratio and ADC value were measured, and percentage change in MRI parameters were calculated. Univariate analysis and multivariate logistic regression analysis were used to evaluate independent predictors of pCR in the training cohort. The validation cohort was used to test the prediction model, and the nomogram was created based on the prediction model. RESULTS: This study demonstrated that the ADC value after two cycles of NAC (ORâ¯=â¯1.041, 95% CI (1.002, 1.081); pâ¯=â¯0.037), percentage decrease in E90 (ORâ¯=â¯0.927, 95% CI (0.881, 0.977); p =0.004) and percentage decrease in tumor size (ORâ¯=â¯0.948, 95% CI (0.909, 0.988); pâ¯=â¯0.011) were significantly important for independently predicting pCR. The prediction model yielded AUC of 0.939 and 0.944 in the training cohort and the validation cohort, respectively. CONCLUSION: The combined use of dynamic contrast-enhanced MRI and diffusion-weighted imaging could accurately predict pCR after two cycles of NAC. The prediction model and the nomogram had strong predictive value to NAC.
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Neoplasias da Mama , Terapia Neoadjuvante , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Terapia Neoadjuvante/métodos , Nomogramas , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To compare the diagnostic accuracy of an abbreviated protocol (AP) with or without quantitative apparent diffusion coefficient (ADC) values on diffusion-weighted imaging (DWI) and a full diagnostic protocol (FDP) in terms of the Breast Imaging Reporting and Data System (BI-RADS) classification of breast magnetic resonance imaging (MRI). METHODS: Our study sample consisted of 436 patients undergoing breast MRI from January to October 2015 in a clinical setting. The three reviews included a pre-contrast and the first single post-contrast T1-weighted (T1W) sequences (AP1), AP1 combined with quantitative DWI (AP2), and the FDP, the AP1 of which were assessed independently by a junior and senior radiologist. Agreement on the evaluation of the BI-RADS classifications (between the junior and senior radiologists, between AP1 and FDP, and between AP2 and FDP) was assessed using the kappa test statistic. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared between AP1 and FDP plus between AP2 and FDP. Diagnostic parameters of these reviews were examined using the McNemar test. RESULTS: The study included 436 patients, with 251 breast cancers, 99 benign lesions, and 86 patients with benign or no lesions and followed up for at least 24 months. The agreement of the BI-RADS classifications between the junior and senior radiologists was very good (kappa =0.847). The agreement between AP2 and FDP (kappa =0.931) was higher than the agreement between AP1 and FDP (kappa =0.872) on evaluating the BI-RADS benign and malignant classifications. The sensitivity/specificity/PPV/NPV was 95.6%/83.8%/88.9%/93.4% for AP1, 98.0%/83.8%/89.1%/96.9% for AP2, 98.8%/83.8%/89.2%/98.1% for FDP, respectively. CONCLUSIONS: The addition of quantitative DWI to the abbreviated MRI protocol based on the pre-and first post-contrast sequence improved diagnostic performance for characterizing breast lesions. Quantitative DWI may be a useful adjunct to dynamic contrast enhancement (DCE) of breast MRI.
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Sepsis is characterized by persistent systemic inflammation, which can cause multi-organ dysfunction. The poly polymerase-1 inhibitor olaparib possesses anti-inï¬ammatory properties. This study aimed to assess the effects of olaparib (pre- and post-treatments) on sepsis, and to investigate whether it could suppress CD14 expression via the ERK pathway in polymicrobial sepsis and peritoneal macrophages models. Sepsis was induced by cecal ligation and puncture in C57BL/6 male mice. Fifty mice were randomly divided into five groups: The sham group was treated with vehicle or olaparib, the cecal ligation and puncture group with vehicle or with olaparib (5 mg/kg i.p.) 1 h before or 2 h after surgery. Olaparib pretreatment significantly improved the survival of septic mice (P < 0.001). Pre- and post-treatment of mice with olaparib partly alleviated cecal ligation and puncture-induced organ injury by decreasing the amounts of the pro-inflammatory mediators TNF-α and IL-6 as well as bacterial burden in the serum, peritoneal lavage fluid, and organs (P < 0.05). The protective effect of olaparib was associated with CD14 suppression via inhibition of ERK activation. Olaparib facilitated negative regulation of ERK-mediated CD14 expression, which may contribute to multi-organ injury in sepsis.
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Receptores de Lipopolissacarídeos/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Receptores de Lipopolissacarídeos/efeitos dos fármacos , Pulmão/metabolismo , Masculino , CamundongosRESUMO
BACKGROUND: Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI. METHODS: Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model. RESULTS: Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin ß3 or ß5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin ß5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown ß3 integrin significantly decreased survival in ALI mice. Notably, knockdown of ß5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice. CONCLUSION: These findings support the ß3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.
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Sepsis is a major challenge in clinical practice and responsible for high mortality. Recent studies indicated that integrins participated in toll-like-receptor (TLR)-mediated innate immunity. In the present study, we investigated the mechanism of integrin ß3 and TLR4 signaling using a cecal ligation and puncture (CLP)-induced sepsis and lipopolysaccharide (LPS)-treated macrophage cell model. In a lethal CLP model, the survival rate of integrin ß3 mice was higher than that of wild-type mice. The levels of alanine aminotransferase, aspartate transaminase, creatinine, blood urea nitrogen , and lactate dehydrogenase in the serum and cluster of differentiation 14 (CD14) protein expression in the tissues were significantly decreased in integrin ß3 mice. A similar effect with regard to CD14 down-regulation was observed in septic TLR4 mice. In wild-type macrophages, the inhibition of integrin ß3 by P11 or with a specific antibody, inhibited TNF-α, and IL-6 release at the early time period of LPS stimulation. However, during the late periods of LPS stimulation this effect was not noted. CD14 expression levels had no change in such treatment. In contract, LPS-induced TNF-α and IL-6 release and LPS-induced CD14 expression were significantly decreased in integrin ß3macrophages. The inhibition of the TLR4 pathway by TAK-242, or in TLR4 mutant macrophages abolished LPS-induced CD14 expression. Integrin ß3 pathway activation by vitronectin exhibited no effect in CD14 expression. Furthermore, recombinant CD14 protein stimulation reversed integrin ß3 deficiency and caused lower TNF-α and IL-6 release. Moreover, the molecular interaction of TLR4 and integrin ß3 was significantly increased following LPS stimulation. In conclusion, integrin ß3 positively regulated TLR4-mediated inflammatory responses via CD14 expression in macrophages in septic condition. Specifically targeting integrin ß3/TLR4-CD14 signaling pathway may be a potential treatment strategy for polymicrobial sepsis.
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Integrina beta3/fisiologia , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Sepse/metabolismo , Receptor 4 Toll-Like/fisiologia , Animais , Modelos Animais de Doenças , Mediadores da Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Sepse/etiologia , Sepse/patologia , Transdução de SinaisRESUMO
The cholinergic antiinflammatory pathway is considered an attractive approach for the alleviation of inflammatory diseases. Sepsis is characterized by systemic inflammation and widespread organ injury, especially that in the lung. In the present study, we explored the effects of an α7nAChR agonist, PNU282987, on sepsisinduced lung injury and investigated the mechanisms of PNU282987 in response to lipopolysaccharide (LPS) stimulation in peritoneal macrophages. Sepsis was induced in C57BL/6 mice via cecal ligation puncture (CLP). Fifty mice were randomly divided into five groups: The sham group treated with vehicle, the sham group treated with PNU282987, the CLP group treated with vehicle, and the CLP group treated with PNU282987 (1 mg/kg) 1 h before or 2 h after surgery. All mice were sacrificed at 12 or 24 h after CLP. Both pre and postCLP treatment with PNU282987 significantly attenuated sepsisinduced lung injury and the release of IL6 in the bronchoalveolar lavage fluid (BALF). Pretreatment with PNU282987 also inhibited sepsisincreased TNFα and IL6 production, while postCLP treatment only inhibited IL6 production in the lung tissue. Neither pre nor postCLP treatment with PNU282987 affected IL6 release in the serum. Furthermore, pretreatment with PNU282987 resulted in reductions in TNFα and IL6 release in a dose and timedependent manner and decreased the phosphorylation levels of p38, JNK and ERK under LPS conditions in peritoneal macrophages. Our results demonstrate that activation of α7nAChR alleviates sepsisinduced lung injury; this effect is associated with the suppression of inflammatory responses via the MAPK pathway, suggesting that α7nAChR is a potential therapeutic target for the treatment of sepsis.
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Lesão Pulmonar Aguda/prevenção & controle , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Modelos Animais de Doenças , Macrófagos Peritoneais/efeitos dos fármacos , Sepse/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Mechanical ventilation (MV) is frequently employed to manage respiratory failure in sepsis patients and is required for the surgical management of intra-abdominal sepsis. The impact of MV varies dramatically depending on tidal volume, with even moderate tidal volume (MTV) ventilation leading to ventilator-induced lung injury, whereas low tidal volume (LTV) ventilation protects against sepsis-induced acute respiratory distress syndrome. Interleukin (IL)-33 is known to contribute to lung injury in sepsis and its release can be induced by mechanical stress. To determine the relationship between the IL-33-suppression of tumorigenicity 2 (ST2) pathway and patterns of lung injury associated with MV in sepsis, mice were subjected to cecal ligation and puncture (CLP) followed 6 h later by either MTV (10âmL/kg) or LTV (6âmL/kg) ventilation for 4 h. MTV and LTV ventilation alone for 4 h had no impact on lung injury. MTV markedly exacerbated lung injury and inflammation, while LTV significantly suppressed these parameters in septic mice. Lung and plasma levels of IL-33 ST2 were significantly elevated by CLP alone at 10âh. MTV caused further and significant increases in IL-33 and sST2 levels, while LTV significantly suppressed levels induced by CLP. Deletion of IL-33 or ST2 prevented the increase in lung injury and inflammation induced by MTV in septic mice, while administration of recombinant IL-33 in the airway reversed the protection seen with LTV. Taken together, these findings implicate the IL-33-ST2 pathway in the pro-inflammatory changes induced by the mechanical ventilation that leads to lung injury in the setting of intra-abdominal sepsis in a tidal volume-dependent manner.
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Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/metabolismo , Sepse/metabolismo , Transdução de Sinais , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Masculino , Camundongos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/fisiopatologia , Sepse/patologia , Sepse/fisiopatologia , Sepse/terapia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologiaRESUMO
Mechanical ventilation (MV) can augment sepsis-induced organ injury. Previous studies indicate that human mesenchymal stem cells (hMSCs) have immune-modulatory effect. We hypothesize that human adipose tissue-derived stromal cells (hADSCs) could attenuate MV and sepsis-induced organ injury. Male C57BL/6 mice were randomized to five groups: Sham group; MV group; cecal ligation and puncture (CLP) group; CLP + MV group; and CLP + MV + hADSC group. Anesthetized mice were subjected to cecal ligation and puncture surgery. The mice then received mechanical ventilation (12 ml/kg), with or without the intervention of hADSCs. The survival rate, organ injury of the liver and kidney, total protein and cells in bronchoalveolar lavage fluid (BALF), and histological changes of the lung and liver were examined. The level of IL-6 in BALF was measured by ELISA. Real-time quantitative PCR was used to analyze mRNA of IL-6 and tumor necrosis factor-α (TNF-α). hADSC treatment increased survival rate of septic mice with MV. hADSCs attenuated dysfunction of the liver and kidney and decreased lung inflammation and tissue injury of the liver and lung. IL-6 level in BALF and TNF-α and IL-6 mRNA expression in the tissue of the lung, liver, and kidney were significantly reduced by hADSC treatment. MV with conventional tidal volume aggravates CLP-induced multiple organ injuries. hADSCs inhibited the compound injuries possibly through modulation of immune responses.
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Insuficiência de Múltiplos Órgãos/terapia , Respiração Artificial/efeitos adversos , Sepse/complicações , Células Estromais/transplante , Tecido Adiposo/citologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/análise , Humanos , Rim/lesões , Fígado/lesões , Fígado/patologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Respiração Artificial/mortalidade , Sepse/mortalidade , Taxa de SobrevidaRESUMO
This study aimed to analyze the correlation between mammographic density obtained by density analysis software (DAS)/radiologists visual (RV) classification with molecular subtype, and the expression levels of estrogen receptor (ER), progesterone receptor (PR), Ki67 antigen (Ki-67), p53 gene (p53), and human epidermal growth factor receptor-2 (HER2). A total of 688 breast cancer patients with digital mammography and complete molecular pathological results in Tianjin Medical University Cancer Institute and Hospital between February 2015 and February 2016 were collected. The DAS-density grade (DASD) and the radiologists visually classified density grade (RVD) were evaluated by 3 radiologists. The correlation between density grade and the expression levels of ER, PR, Ki-67, p53, HER2 and breast cancer molecular subtype (PMS) were analyzed. The agreement between DASD and RVD was explored. ER, PR and HER-2 positive rate were significantly different among patients with different RVD grades (P< 0.05). HER2 positive rates showed an increasing trend following RVD upgrading (Pð¡ðððð< 0.05). HER-2 positive rate in RVD D1 + D2 was 7.69%, which was higher than that in D3 + D4 (P< 0.05). The ER and Ki-67 expressions in patients were markedly different among DASD (P= 0.009 and 0.002) and RVD (P= 0.012 and 0.036) with different grades. The kappa value of each DASD to RVD was 0.31 (P< 0.01). The RVD 3 proportion was 14.58% (63/432) in HER2 Over-expressing subtype, which was apparently higher than RVD1 (2.43%, 1/41) (P< 0.05). Breast density may be partial correlated with molecular pathology in breast cancer.
Assuntos
Biomarcadores Tumorais , Densidade da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Adulto , Idoso , Neoplasias da Mama/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Mamografia , Pessoa de Meia-Idade , Razão de ChancesRESUMO
An overwhelming immune response, particularly from macrophages, plays a critical role in survival and organ damage in sepsis patients. Toll-like receptors (TLRs) are important receptors to recognize the conserved motifs expressed by invading bacteria. The TLRs except TLR3 signal via a MyD88-dependent pathway. TLR3 uses a TRIF-dependent pathway, while TLR4 uses both MyD88 and TRIF-dependent pathways. Previous studies indicated that CD14 was necessary for TLRs-dependent production of pro-inflammatory cytokines. Blocking CD14 protected against the deleterious systemic inflammatory response associated with sepsis. The aim of this study was to determine the signaling pathway of TLR activation-induced CD14 expression in models of polymicrobial sepsis and in peritoneal macrophages. We found that CD14 expression was upregulated in the lung, liver, and kidney of septic mice induced by cecal ligation puncture. In cultured peritoneal macrophages, specific agonists for all TLRs, except for TLR3, increased CD14 expression. Lipopolysaccharide-induced upregulation of CD14 was abolished in peritoneal macrophages from MyD88 KO mice but increased in TRIF inhibitor, resveratrol pretreated wild-type macrophages. Moreover, MyD88 KO, but not TRIF KO mice, showed a decreased CD14 expression in the tissue of septic mice, which was associated with a strongly attenuated inflammatory response and increased survival rate. These data suggest that a MyD88-dependent and TRIF-independent pathway of TLR is activated in upregulating CD14 expression under septic conditions. This study deciphers a critical cross-talk between TLRs and CD14.