miR-130b regulates B cell proliferation via CYLD-mediated NF-κB signaling.

Previous studies have revealed that B cell activation is regulated by various microRNAs(miRNAs). However, the role of microRNA-130b regulating B cell activation and apoptosis is still unclear. In the present study, we first found that the expression of miR-130b was the lowest in Pro/Pre-B cells and the highest in immature B cells. Besides, the expression of miR-130b decreased after activation in B cells. Through the immuno-phenotypic analysis of miR-130b transgenic and knockout mice, we found that miR-130b mainly promoted the proliferation of B cells and inhibited B cell apoptosis. Furthermore, we identified that Cyld, a tumor suppressor gene was the target gene of miR-130b in B cells. Besides, the Cyld-mediated NF-κB signaling was increased in miR-130b overexpressed B cells, which further explains the enhanced proliferation of B cells. In conclusion, we propose that miR-130b promotes B cell proliferation via Cyld-mediated NF-κB signaling, which provides a new theoretical basis for the molecular regulation of B cell activation.

DTX3L Enhances Type I Interferon Antiviral Response by Promoting the Ubiquitination and Phosphorylation of TBK1.

Studies already revealed that some E3 ubiquitin ligases participated in the immune response after viral infection by regulating the type I interferon (IFN) pathway. Here, we demonstrated that type I interferon signaling enhanced the translocation of ETS1 to the nucleus and the promoter activity of E3 ubiquitin ligase DTX3L (deltex E3 ubiquitin ligase 3L) after virus infection and thus increased the expression of DTX3L. Further experiments suggested that DTX3L ubiquitinated TBK1 at K30 and K401 sites on K63-linked ubiquitination pathway. DTX3L was also necessary for mediating the phosphorylation of TBK1 through binding with the tyrosine kinase SRC: both together enhanced the activation of TBK1. Therefore, DTX3L, being an important positive-feedback regulator of type I interferon, exerted a key role in antiviral response. IMPORTANCE Our present study evaluated DTX3L as an antiviral molecule by promoting IFN production and establishing an IFN-ß-ETS1-DTX3L-TBK1 positive-feedback loop as a novel immunomodulatory step to enhance interferon signaling and inhibit respiratory syncytial virus (RSV) infection. Our finding enriches and complements the biological function of DTX3L and provides a new strategy to protect against lung diseases such as bronchiolitis and pneumonia that develop with RSV.

Etiology and clinical features of infection-associated plastic bronchitis in children.

OBJECTIVE: To investigate the etiological characteristics of plastic bronchitis (PB) caused by pulmonary infections in children and to identify any differences in the clinical features of PB cases caused by different pathogens. METHOD: We collected data on children diagnosed with PB and admitted to the Respiratory Department at Soochow University Children's Hospital between July 2021 and March 2023 utilizing electronic bronchoscopy. We analyzed clinical characteristics and the species of pathogens causing the illness in these children. RESULT: A total of 45 children were enrolled. The main clinical symptoms observed were cough (100%), fever (80%), shortness of breath (28.9%), and wheezing (20.0%). Pathogens were identified in 38 (84.4%) patients. Mycoplasma pneumoniae (MP) had the highest detection rate at 53.3%, followed by the Boca virus at 26.7%. MP-induced PB typically occurs in older children with an average age of 7.46 ± 2.36 years, with the main symptoms including high fever (85.7%) and local hyporespiration (42.9%). In contrast, Boca virus-induced PB tends to occur in younger children, with the main symptoms of moderate fever (54.5%), and wheezing (54.5%). The MP group exhibited a higher incidence of both internal and external pulmonary complications, including pleural effusion (42.9%), elevated aspartate aminotransferase (52.4%), lactic dehydrogenase (76.2%), and D-D dimer (90.5%). Conversely, the Boca virus group primarily showed pulmonary imaging of atelectasis (81.8%), with no pleural effusion. The average number of bronchoscopic interventions in the MP group was 2.24 ± 0.62, which was significantly higher than that required in the Boca virus group (1.55 ± 0.52). During the second bronchoscopy, 57.1% of children in the MP group still had visible mucus plugs, while none were observed in the Boca virus group. CONCLUSION: MP and Boca virus are the primary pathogens responsible for PB among children. The clinical manifestations of PB typically vary significantly based on the pathogen causing the condition.

MiR-493-5p inhibits Th9 cell differentiation in allergic asthma by targeting FOXO1.

The role of micro RNAs (miRNAs) in asthma remains unclear. In this study, we examined the role of miRNA in targeting FOXO1 in asthma. Results showed that miR-493-5p was one of the differentially expressed miRNAs in the PBMCs of asthmatic children, and was also associated with Th cell differentiation. The miR-493-5p expression decreased significantly in the OVA-induced asthma mice than the control groups. The miR-493-5p mimic inhibited the expression of the IL-9, IRF4 and FOXO1, while the inhibitor restored these effects. Moreover, the Dual-Luciferase analysis results showed FOXO1 as a novel valid target of miR-493-5p. According to the rescue experiment, miR-493-5p inhibited Th9 cell differentiation by targeting FOXO1. Then the exosomes in association with the pathogenesis of asthma was identified. Various inflammatory cells implicated in asthmatic processes including B and T lymphocytes, DCs, mast cells, and epithelial cells can release exosomes. Our results demonstrated that the DC-derived exosomes can inhibit Th9 cell differentiation through miR-493-5p, thus DC-derived exosomal miR-493-5p/FOXO1/Th9 may serve as a potential therapeutic target in the development of asthma.

The molecular mechanism of SARS-CoV-2 evading host antiviral innate immunity.

The newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a global health emergency (COVID-19) because of its rapid spread and high mortality. Since the virus epidemic, many pathogenic mechanisms have been revealed, and virus-related vaccines have been successfully developed and applied in clinical practice. However, the pandemic is still developing, and new mutations are still emerging. Virus pathogenicity is closely related to the immune status of the host. As innate immunity is the body's first defense against viruses, understanding the inhibitory effect of SARS-CoV-2 on innate immunity is of great significance for determining the target of antiviral intervention. This review summarizes the molecular mechanism by which SARS-CoV-2 escapes the host immune system, including suppressing innate immune production and blocking adaptive immune priming. Here, on the one hand, we devoted ourselves to summarizing the combined action of innate immune cells, cytokines, and chemokines to fine-tune the outcome of SARS-CoV-2 infection and the related immunopathogenesis. On the other hand, we focused on the effects of the SARS-CoV-2 on innate immunity, including enhancing viral adhesion, increasing the rate of virus invasion, inhibiting the transcription and translation of immune-related mRNA, increasing cellular mRNA degradation, and inhibiting protein transmembrane transport. This review on the underlying mechanism should provide theoretical support for developing future molecular targeted drugs against SARS-CoV-2. Nevertheless, SARS-CoV-2 is a completely new virus, and people's understanding of it is in the process of rapid growth, and various new studies are also being carried out. Although we strive to make our review as inclusive as possible, there may still be incompleteness.

The function and mechanism of dopamine in the activation of CD4+ T cell.

CONTEXT: It has been demonstrated that dopamine (DA) plays an important role in numerous cellular processes of T cell. Accumulating evidence suggests that the outcomes of T cell treatment with DA is depended on DA concentrations, T cell subtypes and activation states. However, the detail mechanism of DA function on T cell activation or regulatory T cells is largely unclear. OBJECTIVE: This study aims to explore the mechanisms by which DA regulates the activation of CD4+ T cells and the function of Tregs. MATERIALS AND METHODS: T cell proliferation was detected using CCK-8, BrdU incorporation assay or eFluor 450 cell labeling assay, and Western blot were used to detect phosphorylation of p65 and Erk. Nuclear translocation of transcription factors including p65, FOXO1 and NFAT1 were observed under laser confocal microscopy. RESULTS: Our present study demonstrated that DA (17 µM) can directly promote CD4+ T cells activation through D2-like receptors by enhancing the phosphorylation of p65, also can impair regulatory CD4+ T cells (Tregs) stability and suppressive function through D1- and D2-like receptors by inhibiting the expression of FOXO1 and NFAT1, which are the transcriptional factors of FOXP3, and by suppressing the expression of IL-10 in Tregs. Injection of DA can inhibit tumor growth in vivo. CONCLUSIONS: These data indicate a critical role for DA in promotion of CD4+ T helper response, this may applicable in tumor treatment in the future.

[Association of Haemophilus influenzae infection with environmental and climatic factors in Suzhou, China]. / è‹å·žåœ°åŒºæµæ„Ÿå—œè¡€æ†èŒæ„ŸæŸ“ä¸ŽçŽ¯å¢ƒæ°”å€™çš„ç›¸å ³å› ç´ åˆ†æž.

OBJECTIVES: To investigate the epidemiological characteristics of respiratory Haemophilus influenzae (HI) infection in children in Suzhou, China and its association with climatic factors and air pollutants. METHODS: The data on air pollutants and climatic factors in Suzhou from January 2016 to December 2019 were collected. Respiratory secretions were collected from 7 940 children with acute respiratory infection who were hospitalized during this period, and bacterial culture results were analyzed for the detection of HI. A stepwise regression analysis was used to investigate the association of HI detection rate with air pollutants (PM2.5, PM10, NO2, SO2, CO, and O3) and climatic factors (monthly mean temperature, monthly mean humidity, monthly total rainfall, monthly total sunshine duration, and monthly mean wind speed). RESULTS: In 2016-2019, the 4-year overall detection rate of HI was 9.26% (735/7 940) among the children in Suzhou. The children aged <1 year and 1-<3 years had a significantly higher HI detection rate than those aged ≥3 years (P<0.01). The detection rate of HI in spring was significantly higher than that in the other three seasons, and the detection rate of HI in autumn was significantly lower than that in the other three seasons (P<0.001). The multiple linear regression analysis showed that PM10 and monthly mean wind speed were independent risk factors for the detection rate of HI: the detection rate of HI was increased by 0.86% for every 10 µg/m3 increase in the concentration of PM10 and was increased by 5.64% for every 1 m/s increase in monthly mean wind speed. Air pollutants and climatic factors had a lag effect on the detection rate of HI. CONCLUSIONS: HI is an important pathogen for acute respiratory infection in children in Suzhou and is prevalent in spring. PM10 and monthly mean wind speed are independent risk factors for the detection rate of HI.

IL-1 signaling pathway molecules as key markers in childhood asthma.

OBJECTIVE: The prevalence of childhood asthma has been increasing in recent years. This study aims to investigate the involvement of the key molecules of IL-1 (interleukin-1) signaling pathways in pediatric patients with asthma. METHODS: Differentially expressed genes (DEGs) associated with IL-1 signaling pathways were identified with RNA-seq from peripheral blood samples collected from asthmatic or healthy children and were further verified in clinical peripheral blood samples. Cellular models and asthmatic mice were subsequently developed to validate the identified asthmatic markers. RESULTS: Among the DEGs identified by RNA-seq, eight signal transducers associated with the IL-1 signaling network, namely IL-1RN, IL-1ß, IL-1RAP, IRAK3, IL-1R1, MYD88, IRAK2, and PELI1, were found to be substantially upregulated in children with asthma. Interestingly, a significant serially increased expression of four genes (IL-1RN, IL-1RAP, IRAK3, and PELI1) was observed in healthy subjects, patients with chronic persistent asthma and patients with acute exacerbation asthma. In particular, these four genes were continuously overexpressed in recurrent patients. A significant induction of the above four genes was then observed in house dust mite (HDM)-stimulated peripheral blood mononuclear cells (PBMCs) and ovalbumin (OVA)-induced asthmatic mice. In addition, a time-dependent induction of IL-1RAP and PELI1 was also detected in HDM-treated THP-1 cells, an acute monocytic leukemia cell line. CONCLUSIONS: These results demonstrate that IL-1RN, IL-1RAP, IRAK3, and PELI1, which are signal transducers of the IL-1 signaling pathway, could serve as biomarkers for the pathogenesis of childhood asthma and for potential therapeutic targets of asthma.

Metabolomics reveals a correlation between hydroxyeicosatetraenoic acids and allergic asthma: Evidence from three years' immunotherapy.

BACKGROUND: Subcutaneous immunotherapy (SCIT) is an effective, safe, preventative treatment for allergic asthma; however, potential biomarkers for monitoring SCIT have rarely been reported. OBJECTIVE: Metabolomics was utilized for the discovery of new biomarkers and analyzing disease pathophysiology of allergic asthma, and it was also applied to determine the metabolomic profiles of serum samples from children with asthma undergoing SCIT and identify potential biomarkers for allergic asthma and its therapeutic monitoring. METHODS: Untargeted metabolomics using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry was performed on 15 asthmatic and 15 healthy pediatric sera to profile carboxylic acids. Statistical analysis combined with pathway enrichment analysis was applied to identify potential biomarkers. Then, targeted metabolomics was performed to study longitudinal changes of eicosanoid profiles on sera from 20 participants with asthma who received SCIT at baseline, 6 months, one, two, and three years (ChiCTR-DDT-13003728). RESULTS: Metabolomic analysis revealed that levels of eicosanoids, particularly 12(S)-hydroxyeicosatetraenoic acid (HETE; AUC = 0.94, p < .0001) and 15(S)-HETE (AUC = 0.89, p = .0028), metabolized from arachidonic acid by lipoxygenase and glutathione peroxidase enzymes, were significantly higher in asthma group than in healthy individuals. Furthermore, levels of these important metabolites increased in the first year of SCIT treatment and then decreased from years one to three, being significantly lower after three years of treatment than baseline levels. CONCLUSION: 12(S)- and 15(S)-HETEs are potential biomarkers to participate in the pathogenesis and treatment of allergic asthma. Moreover, these metabolites may be a new target for biological indicators to monitor the therapeutic effect of SCIT, particularly in the setting of allergic asthma.

Risk factors for recurrent wheezing after bronchiolitis in infants: 2-year follow up in China.

BACKGROUND: Infants with bronchiolitis have an increased risk of developing recurrent wheezing and asthma. However, the risk factors for the development of recurrent wheezing after bronchiolitis remains controversial. Our study was to investigate risk factors of post-bronchiolitis recurrent wheezing. METHODS: Infants with bronchiolitis were enrolled from November 2016 through March 2017. Nasopharyngeal aspirates were obtained for detection of respiratory viruses which were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and direct immunofluorescent assay. Serum cytokines including TSLP, IL2, IL13, TIMP-1, MMP-9, IL33, IL5, IL4, IL25, TNF- α and MIP-1α were measured by flow cytometry. Patients were followed up every 3 months for a duration of 2 years by telephone or at outpatient appointments. RESULTS: We enrolled 89 infants, of which 81 patients were successfully followed up. In total, 22.2% of patients experienced recurrent wheezing episodes. The proportion of patients with history of eczema, systemic glucocorticoid use and patients with moderate-to-severe disease were significantly higher in the recurrent wheezing group than the non-recurrent wheezing group (83.3% vs 52.4%; 66.7% vs 36.5%; 61.1% vs 33.3%, respectively, all P < 0.05); There were no significant differences between patients with and without recurrent wheezing episodes in the levels of TSLP, IL2, IL13, TIMP-1, MMP-9, IL33, IL5, IL4, IL25, TNF- α and MIP-1α (P > 0.05). Logistic regression analysis showed that history of eczema was an independent risk factor for post-bronchiolitis recurrent wheezing (odds ratio [OR] = 5.622; 95% confidence interval [CI], 1.3-24.9; P = 0.023). CONCLUSION: The incidence of recurrent wheezing among infants after contracting bronchiolitis was 22.2% during a 2-year follow-up. History of eczema was the only independent risk factor identified and no correlation was found between the specific virus and disease severity in children with post-bronchiolitis recurrent wheezing.

Fractional Exhaled Nitric Oxide (FeNO) Integrating Airway Hyperresponsiveness (AHR) Examination Promotes Etiologic Diagnosis and Treatment for Children with Chronic Cough.

BACKGROUND Chronic cough is the main reason why parents seek medical treatment for their children. This study aimed to evaluate changes in airway function and inflammation levels and associated values in diagnosing and treating chronic cough. MATERIAL AND METHODS This study involved 118 children with chronic cough, including 45 cough-variant asthma (CVA) patients, 53 upper-airway cough syndrome (UACS) patients, and 20 post-infection cough (PIC) patients. Chronic cough was diagnosed as described by guidelines of the American College of Chest Physicians for evaluating chronic cough. Pulmonary ventilation function and airway hyperresponsiveness (AHR) were evaluated. Fractional exhaled nitric oxide (FeNO) levels and eosinophilic airway inflammation were measured. Eosinophil (EOS) count in sputum was also examined. CVA patients were treated with inhaled glucocorticoids, which have anti-inflammatory effects. RESULTS FeNO and sputum EOS levels were higher in CVA patients compared with UACS and PIC patients (P<0.05). CVA patients demonstrated significantly higher small airway indexes, including 25% forced expiratory flow (FEF), 50% FEF, and 75% FEF, compared with UACS and PIC patients (P<0.05). FeNO level was positively correlated with EOS in sputum (r=0.468, P=0.0001) and cough symptom scores (r=0.402, P<0.05). FeNO, EOS, and cough symptoms were significantly improved in CVA patients after glucocorticoid treatment. AHR was improved in all chronic cough patients after treatment. Cough-relief CVA patients demonstrated significantly higher FeNO levels compared with those without cough relief (P<0.05). CONCLUSIONS FeNO integrating pulmonary function and AHR examination can improve etiologic diagnosis and treatment for chronic cough in children.

[Comparative Study of Clinical Manifestations and Sleep Structure in Children with Obstructive Sleep Apnea-hypopnea Syndrome with Different BMI].

OBJECTIVE: To compare and analyze the clinical manifestations and sleep structure of children with obstructive sleep apnea-hypopneasyndrome (OSAHS) with different body mass index (BMI). METHODS: 452 children who were diagnosed with OSAHS between December 2016 and February 2021 by the Department of Respiratory Medicine, Children's Hospital of Soochow University were included in the study. All of them did polysomnography (PSG). They were divided, according to their BMI, into the normal BMI group, the overweight group, and the obesity group. Their clinical data and PSG results were collected. RESULTS: 287 boys (63.5%) and 165 girls (36.5%) were enrolled, with their age ranging between 3 and 15, and the median age being 5.5 (4.5, 7.0). Their BMI ranged between 12.09 kg/m 2 and 38.48 kg/m 2, with the median being 16.29 kg/m 2. 275 cases (60.8%) had normal BMI, 76 cases (16.8%) were overweight, and 101 cases (22.3%) were obese. There was no significant difference in the distribution of clinical manifestations and severity of OSAHS among the three groups. The duration and proportion of rapid eye movement (REM) stage sleep in the obese group was lower than that of the overweight and the normal BMI groups ( P<0.05). The lowest oxyhemoglobin saturation (LSaO 2) of children in the overweight group was lower than that of the normal BMI group ( P=0.050). The oxygen desaturation index (ODI) of the obese group was higher than that of the normal BMI and the overweight groups ( P<0.05). CONCLUSION: Obesity worsens the degree of hypoxia in children with OSAHS and affects their sleep structure.

Pathogen analysis of pertussis-like syndrome in children.

BACKGROUND: The aim of the study was to identify the pathogens, in addition to bordetella pertussis (B. pertussis), which cause pertussis-like syndrome in children and to compare clinical presentation between those with B. pertussis and pertussis-like syndrome. METHODS: A cross-sectional analysis was conducted from March 2016 to September 2018. In total, 281 children with suspected pertussis infections were enrolled in this study. Multi-pathogen detection was performed. RESULTS: In total, 281 children were enrolled including 139 males and 142 females. Among them, 149 (53.0%) were B. pertussis positive, and 72 (15.6%) children tested positive for other pathogens. Mycoplasma pneumoniae (MP, 27 cases) was the most common causative pathogen in pertussis-like syndrome, followed by human rhinovirus (HRV, 23 cases), Streptococcus pneumoniae (SP, 13 cases), Haemophilus influenzae (HI, 12 cases) and parainfluenza virus 3 (Pinf-3, 9 cases). Children in the B. pertussis group had a higher rate of vaccination and longer hospital stay (P < 0.05). B. pertussis was more likely to be detected in winter than other pathogens, but this difference was not significant (P = 0.074). The number of white blood cells, neutrophils and blood platelets was significantly higher in children in the B. pertussis than in the pertussis-like group (P < 0.05). In addition, the percentage of CD3-CD19+ cells was significantly higher in the B. pertussis group (P = 0.018). CONCLUSION: About half of the children with pertussis-like syndrome were B. pertussis positive. MP was the second most common causative pathogen followed by HRV, SP, HI and Pinf-3. Children infected with B. pertussis had longer hospital stay and higher numbers of white blood cells, neutrophil and blood platelets compared with other pathogens.

Value of multi-slice spiral computed tomography for diagnosis of tracheobronchial foreign body aspiration in children: 5-year retrospective study.

BACKGROUND: Tracheobronchial foreign body (TFB) aspiration is a significant cause of respiratory problems in children. The timely diagnosis of TFB is important to decrease the mortality rate and the incidence of complications. Advances in radiology have led multi-slice spiral computed tomography (MSCT) to become the best technique for diagnosing TFB. METHODS: We performed a retrospective study over 5 years from July 2008 to June 2013. We collected information on children who were diagnosed with a TFB by bronchoscopy, and analyzed age, sex, location, type of foreign body, and various MSCT manifestations. RESULTS: A total of 382 children were included and 68.6% of them were aged 1 to <2 years. The majority (95.8%) of aspirated foreign bodies were vegetation items, and nearly half (47.6%) of them were peanut kernels, followed by sunflower seeds (26.2%). A total of 4.7% of TFBs were in the trachea, 51.0% were in the left main bronchus, and 44.2% were in the right main bronchus. Among the TFBs, 359 (95.5%) showed a high-density shadow in the tracheal / bronchial lumen using MSCT, which could establish the presence of a foreign body directly. Emphysema, localized obstruction and pneumonia were more commonly detected in the 7-21 days and ≥21 days group compared with those in the <7 days group (all P < 0.01). Bronchiectasis was found in two children who were diagnosed at least 21 days after aspiration. CONCLUSIONS: Multi-slice spiral computed tomography is very sensitive to TFBs. Timely diagnosis and treatment of TFB is important to prevent long-term sequelae in children.

High co-expression of TNF-α and CARDS toxin is a good predictor for refractory Mycoplasma pneumoniae pneumonia.

BACKGROUND: Early distinction between refractory M. pneumoniae pneumonia (RMPP) and non-RMPP (NRMPP) is still difficult. The community-acquired respiratory distress syndrome (CARDS) toxin can induce inflammatory and histopathological phenotypes associated with M. pneumoniae infection. This study aimed to investigate the clinical significance of CARDS toxin and pro-inflammatory cytokines in children with RMPP and to explore whether CARDS toxin can induce TNF-α expression. METHODS: Levels of CARDS toxin and cytokines in BALF from control and children with MPP were determined by real-time PCR and ELISA, respectively. A receiver-operating characteristic (ROC) analysis was performed to assess the diagnostic values of CARDS toxin, TNF-α, and IL-6 in RMPP. The recombinant CARDS toxin was constructed and prepared at different concentrations for stimulation of RAW264.7 cells. After co-culture with CARDS toxin, cytokines were detected by ELISA and the mRNA levels were measured by real-time PCR. Effects of CARDS toxin and TNF-α on inflammatory cell infiltration and mucus secretion in mouse lungs were also evaluated. RESULTS: Levels of CARDS toxin, TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF) were significantly higher in RMPP cases compared with NRMPP cases. Furthermore, TNF-α had better diagnostic ability for differentiation of RMPP with AUC of 0.824 and Youden index of 0.692 compared with CARDS toxin and IL-6. Moreover, CARDS toxin was positively correlated with TNF-α level in MPP cases. In vitro assay revealed that CARDS toxin induced RAW264.7 macrophages to secrete TNF-α. Further in vivo assay showed that TNF-α deletion partially abrogated the CARDS toxin-mediated induction of inflammatory cell infiltration and mucus secretion in mouse lungs. CONCLUSIONS: The high co-expression of TNF-α and CARDS toxin in BALF is a good diagnostic biomarker for differentiating children with RMPP and NRMPP.

LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis.

Myeloid-derived suppressor cells (MDSCs) represent a group of immature myeloid cells composed of myeloid progenitor cells and immature myeloid cells that can negatively regulate immune responses by inhibiting T-cell function. In mice, MDSCs are broadly defined by the expression of CD11b and Gr1. We and others have shown that injection of a lethal or sublethal dose of lipopolysaccharide (LPS) into mice could result in the expansion of MDSCs in the bone marrow (BM), spleen and blood. Until now, the molecular mechanisms responsible for this expansion are poorly studied; specifically, the roles of the individual microRNAs (miRNAs) which may be involved remain largely unknown. We performed microarray analysis to compare the miRNA expression profiles of CD11b+ Gr1+ cells sorted from the BM of LPS-injected and phosphate-buffered saline-injected mice. We identified let-7e, which was highly upregulated in the LPS-treated group, as a potent regulator of LPS-induced MDSC expansion. Furthermore, let-7e overexpression in BM chimeric mice led to a noticeable increase in the population of CD11b+ Gr1+ cells, which resulted from reduced cellular apoptosis. Further studies showed that let-7e could directly target caspase-3 to inhibit cell apoptosis, and upregulation of let-7e in LPS-stimulated MDSCs could be due to the relieved repression of let-7e transcription exerted by downregulated GATA2. Our findings suggest that LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis.

Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo.

Tumor-derived exosomes (TEX) play an important role in the escape of tumor cells from immune surveillance. However, the details of the mechanism are not fully understood. In this study, the apoptosis of CD4+ T cells increased during treatment with B16-derived exosomes in vitro and in vivo, resulting in accelerated growth of melanoma cells in mice. While the release of exosomes was blocked by disrupting the expression of Rab27a, tumor growth was clearly inhibited, and the percentage of T cells in the tumor environment increased. At the same time, Western blot showed that TEX could increase the activation of caspase-3, caspase-7 and caspase-9 but not caspase-8, down-regulating the anti-apoptotic proteins, including BCL-2, MCL-1 and BCL-xL in CD4+ T cells, and indicating that the TEX activates the mitochondrial apoptotic pathway of CD4+ T cells. These reductions were probably associated with the release of microRNAs, such as miR-690, from TEX to T cells. Our present study reveals for the first time that melanoma-released exosomes may directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo.

Fractional Exhaled Nitric Oxide (FeNO) Combined with Pulmonary Function Parameters Shows Increased Sensitivity and Specificity for the Diagnosis of Cough Variant Asthma in Children.

BACKGROUND Cough variant asthma in children presents with a dry nonproductive cough. This study aimed to investigate the diagnostic value of fractional exhaled nitric oxide (FeNO) combined with small airway functional parameters in cough variant asthma. MATERIAL AND METHODS Children with asthma (n=136) were divided into a cough variant asthma (CVA) group (n=57; mean age, 8.03±2.1 years) and a non-cough variant asthma (nCVA) group (n=79; mean age, 8.61±1.7 years). In both groups, FeNO and other pulmonary function parameters were measured including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF), forced expiratory flow (FEF), and maximum expiratory flow at 25%, 50%, and 75% expired volume (MEF25, MEF50, and MEF75). Receiver-operating characteristic (ROC) curve analysis compared the sensitivity and specificity between the diagnostic parameters. RESULTS The FeNO values were significantly increased in the CVA group compared with the nCVA group (Z=6.890, p<0.001). The MMEF, MEF25, MEF50, and MEF75 values were significantly lower in the CVA group compared with the nCVA group (p=0.000, p=0.014, p=0.000, and p=0.000, respectively). The FeNO values were negatively correlated with MEF25, MEF50, and MMEF (ρ=-0.334, ρ=-0.257 and ρ=-0.276, respectively). FeNO was significantly more efficient diagnosing cough variant asthma comparing with pulmonary parameters (p<0.05), and was most sensitive and specific when combined with MMEF/MEF50 compared with single diagnostic parameters (p<0.05). CONCLUSIONS FeNO combined with pulmonary function parameters of MMEF/MEF50 showed increased sensitivity and specificity for the diagnosis of cough variant asthma.

Impact of RSV Coinfection on Human Bocavirus in Children with Acute Respiratory Infections.

OBJECTIVE: The objective of this study was to assess epidemiological and clinical features of human bocavirus (HBoV) coinfection with other viruses. METHOD: Children coinfected with HBoV between January 2012 and December 2014 were enrolled and retrospectively reviewed. RESULT: A total of 984 patients were stratified into five groups: HBoV infection alone (n = 249), respiratory syncytial virus (RSV) infection alone (n = 649), HBoV coinfection with RSV (n = 28), with human rhinovirus (HRV) (n = 39) and with other virus (n = 19). Length of hospitalization was longer in HBoV coinfection with RSV group than HBoV (9.0 days vs. 7.0 days, p = 0.001), RSV (9.0 days vs. 8.0 days, p = 0.016) infection alone group. Pneumonia was more common in the HBoV coinfection with RSV group compared with the HBoV, RSV infection alone group, respectively (75.0% vs. 44.2%, 31.3%, p < 0.001). HBoV DNA copy numbers (383 000 copies/ml) were positively correlated with the length of hospitalization (r = 0.334, p < 0.001). CONCLUSION: HBoV coinfection with RSV increases HBoV infection severity.

[Detection of viral pathogens and allergens in infants and young children at high risk of asthma during a wheezing episode].

OBJECTIVE: To investigate the viral etiology and allergen distribution in infants and young children at high risk of asthma during a wheezing episode. METHODS: A total of 135 infants and young children at high risk of asthma were enrolled who were admitted due to asthmatic bronchitis or asthmatic bronchopneumonia between April 2016 and August 2017. Fluorescent probe PCR was used to measure influenza A (Flu A), respiratory syncytium virus (RSV), adenovirus (ADV), parainfluenza virus (PinF), human rhinovirus (HRV), human partial lung virus (hMPV) and human bocavirus (HBoV) in nasopharyngeal aspirates. ImmunoCAP was used to measure inhaled allergens, food allergens, and total IgE concentration. RESULTS: Among the 135 patients, the overall virus detection rate of nasopharyngeal aspirates was 49.6%, and HRV had the highest detection rate of 25.2%, followed by HBoV (9.6%), RSV (8.1%), PinF (5.9%), Flu-A (3.7%), ADV (1.5%) and hMPV (0.7%). The 1-3 years group had a significantly higher detection rate of HRV than the <1 year group (P<0.05). The positive rate of allergen screening was 59.3%, with 44% for inhaled allergens and 89% for food allergens. Among the inhaled allergens, dust mites had the highest positive rate of 77%, followed by mould (37%), pollen (26%) and animal dander (9%). Among the food allergens, egg white had a positive rate of 73% and milk had a positive rate of 68%. The <1 year group had a significantly higher positive rate of inhaled allergens than the 1-3 years group (P<0.05). The 1-3 years age group had a significantly higher level of T-IgE than the <1 year group (P<0.05). The positive virus group had a significantly higher positive rate of inhaled allergens than the non-virus group (P<0.05). The children with the second wheezing episode had significantly higher positive rates of inhaled allergens and food allergens and level of T-IgE than those with the first wheezing episode (P<0.05). The children with the second wheezing episode also had significantly higher positive rates of dust mites and mould than those with the first wheezing episode (P<0.05). CONCLUSIONS: Early HRV infection and inhaled allergen sensitization are closely associated with the development of wheezing in infants and young children at high risk of asthma.