A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells. METHODS: We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×109 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored. RESULTS: Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×109 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×109 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56dimCD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased. CONCLUSIONS: In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).

Characteristics and outcomes of COVID-19 in Chinese immune thrombocytopenia patients: A prospective cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has a significant impact on the immune system. This is the first and largest study on pre-existing immune thrombocytopenia (ITP) patients infected with COVID-19 in China. We prospectively collected ITP patients infected with COVID-19 enrolled in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) and followed up for at least 1 month after infection. One thousand and one hundred forty-eight pre-existing ITP patients were included. Two hundred and twelve (18.5%) patients showed a decrease in the platelet (PLT) count after infection. Forty-seven (4.1%) patients were diagnosed with pneumonia. Risk factors for a decrease in the PLT count included baseline PLT count <50 × 109/L (OR, 1.76; 95% CI, 1.25-2.46; p = 0.001), maintenance therapy including thrombopoietin receptor agonists (TPO-RAs) (OR, 2.27; 95% CI, 1.60-3.21; p < 0.001) and previous splenectomy (OR, 1.98; 95% CI, 1.09-3.61; p = 0.03). Risk factors for pneumonia included age ≥40 years (OR, 2.45; 95% CI, 1.12-5.33; p = 0.02), ≥2 comorbidities (OR, 3.47; 95% CI, 1.63-7.64; p = 0.001), maintenance therapy including TPO-RAs (OR, 2.14; 95% CI, 1.17-3.91; p = 0.01) and immunosuppressants (OR, 3.05; 95% CI, 1.17-7.91; p = 0.02). In this cohort study, we described the characteristics of pre-existing ITP patients infected with COVID-19 and identified several factors associated with poor outcomes.

Molecular analysis of phenotypic heterogeneity in JAK2V617F-positive myeloproliferative neoplasms reveals a potential target for therapy.

JAK2V617F is the most frequent mutation in BCR-ABL-negative myeloproliferative neoplasms (MPNs). It is an important but not the only determinant of MPN phenotype. We performed high-throughput sequencing on JAK2V617F+ essential thrombocythaemia (ET) and polycythaemia vera (PV) patient samples to unveil factors involved in phenotypic heterogeneity and to identify novel therapeutic targets for MPN. Two concurrent mutations that may affect phenotype were identified, including mutations in SH2B3, which is primarily prevalent in PV, and SF3B1, which is more commonly mutated in ET. Next, we conducted transcriptomic analysis at the haematopoietic stem cell (HSC) and megakaryocyte (MK)-erythroid progenitor (MEP) levels. Inflammatory signalling pathways were elevated in both ET HSCs and MEPs, unlike in PV HSCs and MEPs. Notably, Wnt/ß-catenin signalling was uniquely upregulated during ET haematopoietic differentiation from HSC to MEP, and inhibiting Wnt/ß-catenin signalling blocked MK differentiation in vitro. Consistently, Wnt/ß-catenin inhibitor administration decreased platelet counts in JAK2V617F+ MPN mice by blocking MEPs and MK progenitors and by inhibiting maturation of MKs, while in wild-type mice, Wnt/ß-catenin inhibitor did not significantly reduce platelet counts. In conclusion, our findings provide new insights into the mechanisms underlying phenotypic differentiation of JAK2V617F+ PV and ET and indicate Wnt/ß-catenin signalling as a potential therapeutic target for MPN.

Asymmetric Bio-epoxidation of Unactivated Alkenes.

Optically active epoxides play important roles in pharmaceutical, agricultural and fine chemical syntheses. There are many chiral medications with pharmacodynamic activity in nature that can be synthesized by chiral epoxides. In recent years, researchers have developed a variety of biocatalysts for the asymmetric epoxidation of alkenes, which use oxygen or hydrogen peroxide as eco-friendly and low-cost oxidants, to provide better chemo-, regio- and stereoselectivity under moderate reaction conditions. In this paper, the advances, opportunities and challenges of the asymmetric epoxidation of unactive alkenes by biocatalyst are reviewed.

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.

Busulfan for Allogeneic Hematopoietic Stem Cell Transplantation in Children with Severe Aplastic Anemia: A Retrospective Study.

INTRODUCTION: This retrospective study aimed to compare a range of conditioning regimens in children with severe aplastic anemia (SAA) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the Seventh Medical Center of PLA General Hospital between January 2008 and June 2017. METHODS: Patients were categorized into the Bu (Bu + Flu + Cy + ATG-F regimen) and control (Flu + Cy + ATG-F) groups, with a median follow-up time after HSCT of 3.5 (range, 3.1-6.2) and 3.7 (3.2-5.9) years in the Bu and control groups, respectively. RESULTS: No differences were observed between the two groups regarding the median time of peripheral blood neutrophil and platelet engraftment (p = 0.538 and p = 0.491); the 28-day engraftment rates of neutrophils were similar (p = 0.199), although higher for platelets with Bu (p = 0.044). Additionally, graft failure was 0% and 20.0% in the Bu and control groups, respectively (p = 0.004). In both groups, the incidence of grades III-IV (or grades II-IV) acute graft-versus-host disease (GVHD) and chronic GVHD was not significantly different (p > 0.05). Moreover, the 3-year overall survival and failure-free survival did not show significant differences (p = 0.670 and p = 0.908). DISCUSSION: In children with SAA undergoing allo-HSCT, conditioning regimen with Bu + Flu + Cy + ATG-F is capable of enhancing the myeloablation effect, promoting donor hematopoietic stem cell engraftment, and reducing the graft failure rate. Furthermore, it does not increase the incidence of complications, including GVHD.

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.

Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer.

BACKGROUND: Progestin is used for fertility-sparing treatment in cases of endometrial cancer (EC). Progestin can induce hyperprolactinemia by increasing pituitary secretion and endometrial decidualization. However, progestin induces prolactin (PRL) secretion, which stimulates cell proliferation and deleteriously affects treatment. To date, the detrimental effect of PRL, the secretion of which is induced by medroxyprogesterone acetate (MPA) during fertility-sparing treatment, has not yet been fully elucidated. Therefore, we aimed to assess the effects of PRL on EC cells during combined treatment with progestin and metformin. METHODS: In total, 71 patients with EC/endometrial atypical hyperplasia who underwent fertility-sparing treatment at our institution from 2009-2019 were enrolled. Serum PRL levels were determined using enzyme immunoassays; mRNA levels in endometrial tissues were determined using quantitative reverse-transcription PCR. To evaluate MPA-induced decidualization, cancer-associated stromal cells were enzymatically released from surgically removed specimens of six patients with EC. To examine PRL-induced cell proliferation, the EC cell lines Ishikawa, HEC1B, and HEC265 were used. In vitro cell proliferation was evaluated using the WST assay; protein levels of signaling molecules were determined using western blotting. RESULTS: MPA administration significantly increased serum PRL levels at 3 and 6 months and upregulated IGFBP-1 and PRL mRNA expression in tissues at 3 months of fertility-sparing treatment. Metformin significantly reduced MPA-induced IGFBP-1 and PRL mRNA expression during fertility-sparing treatment and significantly inhibited the upregulation of IGFBP-1 and PRL mRNA and PRL levels due to decidualization induced by MPA and cAMP treatment in primary cultured EC stromal cells. In vitro, PRL increased cell proliferation and ERK1/2 phosphorylation levels, whereas metformin attenuated these increases. CONCLUSIONS: MPA upregulated PRL levels in serum and endometrial tissues during fertility-sparing treatment. Metformin co-administration reduced PRL production and attenuated PRL-induced cell-proliferation activity. This study may provide valuable insights on the application of metformin to improve the outcomes of fertility-sparing treatment.

Advances in the Understanding of the Complex Role of Venous Sinus Stenosis in Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension (IIH) is a disorder characterized by elevated intracranial pressure (ICP) that predominantly affects young obese women. IIH is a diagnosis of exclusion. That is, if increased ICP is suspected, magnetic resonance imaging and magnetic resonance venography of the brain are recommended to exclude secondary causes. Imaging findings, such as empty sella, orbital findings, meningocele, and encephalocele, are not diagnostic of ICP, nor does their absence exclude ICP either. Therefore, venous manometry is recommended as the gold standard for evaluation, regardless of previous anatomic imaging results. Venous manometry is an invasive examination that is frequently applied to derive physiologic information concerning the nature of the pressure gradient. However, the pathogenesis of IIH has not been fully elucidated. The presence of venous sinus stenosis in a subset of patients has provided some support for the potential mechanisms underlying this condition. Hence, this review provides an up-to-date discussion on the potential pathogenic mechanisms of IIH with a special focus on venous sinus stenosis. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

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.

Comparing the contents, functions and neonicotinoid take-up between floral and extrafloral nectar within a single species (Hemerocallis citrina Baroni).

BACKGROUND AND AIMS: Many angiosperms can secrete both floral (FN) and extrafloral (EFN) nectar. However, much remains unclear about how EFN and FN differ in secretion, composition and ecological function, especially when both FN and EFN are secreted on flowers of the same species. METHODS: Hemerocallis citrina flowers secrete both FN and EFN. The FN and EFN traits including volume, presentation pattern and temporal rhythms of secretion were compared by field observation. Sugar and amino acid contents were analysed using regular biochemical methods, whereas the proteome was investigated by combined gel-based and gel-free approaches. Animal feeders on FN and EFN were investigated by field observation. Hemerocallis citrina plants were exposed by soil drenching to two systemic insecticides, acetamiprid and imidacloprid, and the concentration of these in FN and EFN was measured by ultra-high performance liquid chromatography coupled with mass spectrometry. KEY RESULTS: Hemerocallis citrina FN was concentrated and sucrose dominant, secreted in the mature flower tube and served as a reward for pollinators. Conversely, EFN was hexose rich, more dilute and less rich in sugar and amino acids. EFN was secreted on the outside of developing floral buds, and was likely to attract predatory animals for defence. EFN had fewer phenolics, but more pathogenesis-related components, such as chitinase and glucanase. A significantly different proteomic profile and enzymatic activities between FN and EFN suggest that they had different biosynthesis mechanisms. Both neonicotinoid insecticides examined became present in both nectar types soon after application, but in greater concentration within EFN; EFN also attracted a wider range of insect species than FN. CONCLUSIONS: Hemerocallis citrina FN and EFN differed in production, composition and ecological function. The EFN pathway could be a significant way for neonicotinoids to enter the wild food chain, and must be considered when evaluating the risks to the environment of other systemic insecticides.

Identification and quantitation of the novel insecticide sulfoxaflor and its metabolites in floral nectar from Salvia splendens Ker Gawl. (Lamiaceae).

Sulfoxaflor is a new systemic insecticide developed as a replacement for older neonicotinoids which are known to be toxic to pollinators. However, its metabolism in nectar and effect on nectar biosynthesis have not been investigated. After soil and foliar application, sulfoxaflor and its main metabolites in soil, leaf and Salvia splendens nectar, were measured by liquid chromatography coupled with triple quadrupole mass spectrometer (LC-MS/MS). The chemical composition between the clean and sulfoxaflor spiked nectar were also compared. The activities of two possible sulfoxaflor detoxifying enzymes in S. splendens nectar, nitrile hydratase and glutathione-s-transferase, were measured by LC-MS and spectrophotometry. S. splendens nectar proteome was investigated by high-resolution orbitrap-based MS/MS to screen for sulfoxaflor detoxifying relevant proteins. S. splendens could absorb sulfoxaflor through root or leaf surface and secrete a proportion of sulfoxaflor along with its metabolites into the nectar. After soil application, sulfoxaflor's low toxic metabolite X11719474 was dominant in the nectar and reached an average concentration of 8905 ppb. However, after foliar application, sulfoxaflor was dominant over its metabolites in the nectar. S. splendens nectar has no nitrile hydratase and glutathione-s-transferase activity and none of the 106 proteins identified in the nectar were predicted to function in detoxifying sulfoxaflor. Soil and foliar sulfoxaflor application can result in different profiles of sulfoxaflor and its metabolites presented in the nectar. However, sulfoxaflor had no effects on S. splendens nectar secretion and chemical composition and cannot be directly detoxified by components in the nectar.

[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.

Hyperoside relieves particulate matter-induced lung injury by inhibiting AMPK/mTOR-mediated autophagy deregulation.

Autophagy-mediated cell death plays a critical role in the pathogenesis of PMs-induced lung injury. Hyperoside (Hyp), a flavonoid glycosides, is known to exert protective effects on many diseases by inhibiting autophagic activity. The current study aimed to explore the protective effect and mechanism of Hyp against PMs-induced lung injury in PM2.5 challenged Beas-2b cells in vitro and BALB/C mice in vivo. In vitro, we found that the organic solvent-extractable fraction of SRM1649b (O-PMs) caused more severe cytotoxicity in Beas-2b cells than the water solvent-extractable fraction of SRM1649b (W-PMs). O-PMs treatment dose-dependently upregulated the expression of autophagy markers (beclin-1, p62, atg3 and LC3II) and apoptotic proteins. This cytotoxicity of O-PMs was attenuated by Hyp pretreatment in parallel with downregulation of the expression of autophagy markers, apoptotic proteins, and p-AMPK and upregulation of p-mTOR expression. Notably, the therapeutic effect of Hyp was attenuated by pretreated with AICAR (an AMPK inducer), but enhanced by CC and 3-MA treatment. In vivo, Hyp reduced pathological lung injury and decreased the levels of PMs-induced inflammatory cytokines (TNF-α and IL-6), and the number of total cells in the BALF by inhibiting AMPK/mTOR signaling. Furthermore, cotreatment with AICAR (500 mg/kg) reduced but did not abrogate the pulmonary protective effect of Hyp. These findings indicate that Hyp protects against PMs-induced lung injury by suppressing autophagy deregulation and apoptosis through regulation of the AMPK/mTOR pathway.

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.

Differences of clinical features and prognosis between Mycoplasma pneumoniae necrotizing pneumonia and non-Mycoplasma pneumoniae necrotizing pneumonia in children.

BACKGROUND: In the past few years, Mycoplasma pneumoniae (Shi et al. Lancet 390:946-958, 2017) infection has been reported more in China. However, there are few studies on the clinical characteristics and prognosis of necrotizing pneumonia (NP) (Griffiths et al. Nature 583:615-619, 2020) caused by different pathogens. METHODS: A retrospective analysis was performed, including 31 children with a clinical diagnosis of NP in the hospital from January 1, 2013 to January 31, 2020. A total of 11 children with MPNP were included in the observation group and the other 20 children with other pathogens were included in the control group. The clinical manifestations, laboratory data, imaging findings, treatments and outcomes were analyzed. RESULTS: The proportion of dyspnea cases was significantly higher in the non-Mycoplasma pneumoniae necrotizing pneumonia (N-MPNP) group than that in the Mycoplasma pneumoniae necrotizing pneumonia (MPNP) group (P = 0.02).The LDH level of all patients in the MPNP group was higher than the normal value, with a median value of 805.0 U/L, which was significantly higher than those in the N-MPNP group (414.0 [299.9-540.6] U/L; Z = - 2.518; P = 0.012). The white blood cells (WBCs) count of the N-MPNP group was 17.8 (11.1-21.7) × 109/L, which was significantly higher than that of the MPNP group (10.2 [6.3-14.1] × 109/L; P < 0.05). The mean time of pulmonary necrosis in the MPNP group was 20.9 ± 6.9 days, which was higher than that of the N-MPNP group (16.8 ± 6.1 days; t = 3.101; P = 0.004). The incidence of pleural effusion in the N-MPNP group (19 patients, 95%) was significantly higher than that in the MPNP group (six patients, 54.55%) (P = 0.013). Among them, two patients received bronchoscopy lavage at a maximum four times, and the cases of plastic bronchitis were seen only in the MPNP group (3 cases; P = 0.037).The length of stay was 18 (10-22) days in the MPNP group and 23.5 (13.5-47) days in the N-MPNP group and no significant difference was observed between the two groups (Z = - 1.923, P = - 0.055). CONCLUSIONS: 1. MP infection is the most common infection in children with NP in the Suzhou area. There is no gender and age difference between MPNP and N-MPNP, but the bacterial infection was mainly observed in the N-MPNP group. 2. Children in the N-MPNP group have more severe clinical symptoms, were more prone to shortness of breath, had a longer hospital stay, and had earlier imaging manifestations of necrosis, whereas children in the MPNP group were more likely to have plastic bronchitis. The level of WBC and LDH and the nature of pleural effusion can be used to identify MPNP and N-MPNP to some extent. 3. The prognosis of MPNP was better than that of N-MPNP. There were no death cases. Pleural thickening, pulmonary fibrosis, and bronchiectasis were the most common sequelae. Compared with N-MPNP, the recovery time of lung imaging in MPNP was shorter.

Multilevel defects in the hematopoietic niche in essential thrombocythemia.

The role of the bone marrow niche in essential thrombocythemia (ET) remains unclear. Here, we observed multilevel defects in the hematopoietic niche of patients with JAK2V617F-positive ET, including functional deficiency in mesenchymal stromal cells (MSC), immune imbalance, and sympathetic-nerve damage. Mesenchymal stromal cells from patients with JAK2V617F-positive essential thrombocythemia had a transformed transcriptome. In parallel, they showed enhanced proliferation, decreased apoptosis and senescence, attenuated ability to differentiate into adipocytes and osteocytes, and insufficient support for normal hematopoiesis. Additionally, they were inefficient in suppressing immune responses. For instance, they poorly inhibited proliferation and activation of CD4-positive T cells and the secretion of the inflammatory factor soluble CD40-ligand. They also poorly induced formation of mostly immunosuppressive T-helper 2 cells (Th2) and the secretion of the anti-inflammatory factor interleukin-4 (IL-4). Furthermore, we identified WDR4 as a potent protein with low expression and which was correlated with increased proliferation, reduced senescence and differentiation, and insufficient support for normal hematopoiesis in MSC from patients with JAK2V617F-positive ET. We also observed that loss of WDR4 in MSC cells downregulated the interleukin-6 (IL-6) level through the ERK-GSK3ß-CREB signaling based on our in vitro studies. Altogether, our results show that multilevel changes occur in the bone marrow niche of patients with JAK2V617F-positive ET, and low expression of WDR4 in MSC may be critical for inducing hematopoietic related changes.

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.

Exosomes from Thymic Stromal Lymphopoietin-Activated Dendritic Cells Promote Th2 Differentiation through the OX40 Ligand.

OBJECTIVES: Exosomes are extracellular vesicles released from various inflammatory cells, such as T cells, B cells, dendritic cells (DCs), and mast cells, which have been implicated in the modulation of immune response in asthma. This study aimed to investigate whether exosomes from DCs activated by thymic stromal lymphopoietin (TSLP) play a role in T-helper cell differentiation through the OX40 ligand (OX40L). METHODS: Serum samples from patients with asthma were collected to measure the levels of OX40L, T-helper type 1 (Th1) cytokine interferon (IFN)-γ, and T-helper type 2 (Th2) cytokine interleukin (IL)-4 by enzyme-linked immunosorbent assay (ELISA). Exosomes were isolated from TSLP-activated DCs and co-cultured with CD4+ T cells. Western blot and ELISA assays were used to measure the levels of OX40L, IFN-γ, and IL-4 in DCs and CD4+ T cells. Flow cytometry was applied to detect Th1 and Th2 cells. RESULTS: OX40L and IL-4 were increased and IFN-γ was decreased in serum from asthmatic patients compared with healthy controls. TSLP induced DCs to express OX40L in released exosomes, which could promote proliferation of CD4+ T cells, elevate the level of IL-4, and promote Th2 differentiation. CONCLUSION: Blockade of OX40L in DC-derived exosomes could inhibit exosome-mediated CD4+ T proliferation and Th2 differentiation.