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Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces. Specifically, our strategy permits controlled assembly of small poly(ß-amino ester)/messenger ribonucleic acid (mRNA) nanoparticles into particles with a size that is kinetically tunable between 200 and 1,000 nm with high colloidal stability in physiological media. We found that assembled particles with an average size of 400 nm safely and most efficiently transfect monocytes following intravenous administration and mediate their differentiation into macrophages in the periphery. When a CpG adjuvant is co-loaded into the particles with an antigen mRNA, the monocytes differentiate into inflammatory dendritic cells and prime adaptive anticancer immunity in the tumor-draining lymph node. This platform technology offers a unique ligand-independent, particle-size-mediated strategy for preferential mRNA delivery and enables therapeutic paradigms via monocyte programming.
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Monócitos , Nanopartículas , RNA Mensageiro , Monócitos/metabolismo , Nanopartículas/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Camundongos , Humanos , Polieletrólitos/química , Macrófagos/metabolismo , Poliaminas/química , Tamanho da Partícula , Diferenciação Celular , Técnicas de Transferência de Genes , Células Dendríticas/metabolismo , Eletricidade Estática , PolímerosRESUMO
Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second-line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti-CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow-up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 109/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 109/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 109/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 109/L following Dara at ≥75% of the platelet count assessment at follow-up end-point since the patient achieved response) was 48, 175 and 204 days with the follow-up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow-up. No significant treatment-related adverse events were found during follow-up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored.
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Anticorpos Monoclonais , Púrpura Trombocitopênica Idiopática , Humanos , Masculino , Feminino , Criança , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/sangue , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , China , Pré-Escolar , Doença Crônica , Resultado do Tratamento , Contagem de PlaquetasRESUMO
Thrombopoietin (TPO) is the critical regulator of platelet production. However, the role of TPO in pediatric patients with thrombocytopenic disorders has not been fully elucidated. In the present study, we attempted to investigate serum TPO levels in patients with acquired aplastic anemia (aAA) and immune thrombocytopenia (ITP). We analyzed the endogenous plasma concentration of TPO and platelet count at the time of TPO measurement in 166 patients with aAA and 280 patients with ITP retrospectively. We further observed a correlation between platelet counts and TPO. Serum TPO levels were significantly higher in aAA compared with ITP (1142 vs. 77.99 pg/mL, P <0.001). In patients with aAA, an elevation for TPO levels in very severe AA (VSAA) was seen when compared with non-severe AA (NSAA) (1360 vs. 984.4 pg/mL, P <0.05). In contrast, the circulating TPO levels with chronic ITP (CITP) showed a decrease than newly diagnosed ITP (NITP) and persistent ITP (PITP) (62.28 vs. 81.56 pg/mL, P <0.01, 62.28 vs. 87.82 pg/mL, P <0.05, respectively). There was a negative correlation between platelet counts and TPO levels in aAA (r s =-0.3325, P <0.001) as well as ITP (r s =-0.2570, P <0.001). Especially, TPO levels were inversely correlated with platelet counts in NSAA (r s =-0.3672, P <0.001) and NITP (r s =-0.3316, P <0.001). After grouping by age or sex, there were no statistical differences in aAA or ITP. Serum TPO levels were markedly elevated in pediatric patients with aAA compared with ITP. It was higher in VSAA and lower in CITP, suggesting that serum TPO level could play a role in classifying disease severity or clinical course in aAA and ITP.
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Anemia Aplástica , Púrpura Trombocitopênica Idiopática , Trombopoetina , Humanos , Trombopoetina/sangue , Feminino , Masculino , Anemia Aplástica/sangue , Criança , Púrpura Trombocitopênica Idiopática/sangue , Pré-Escolar , Adolescente , Estudos Retrospectivos , Contagem de Plaquetas , LactenteRESUMO
Lipid nanoparticles (LNPs) have recently emerged as successful gene delivery platforms for a diverse array of disease treatments. Efforts to optimize their design for common administration methods such as intravenous injection, intramuscular injection, or inhalation, revolve primarily around the addition of targeting ligands or the choice of ionizable lipid. Here, we employed a multi-step screening method to optimize the type of helper lipid and component ratios in a plasmid DNA (pDNA) LNP library to efficiently deliver pDNA through intraduodenal delivery as an indicative route for oral administration. By addressing different physiological barriers in a stepwise manner, we down-selected effective LNP candidates from a library of over 1000 formulations. Beyond reporter protein expression, we assessed the efficiency in non-viral gene editing in mouse liver mediated by LNPs to knockdown PCSK9 and ANGPTL3 expression, thereby lowering low-density lipoprotein (LDL) cholesterol levels. Utilizing an all-in-one pDNA construct with Strep. pyogenes Cas9 and gRNAs, our results showcased that intraduodenal administration of selected LNPs facilitated targeted gene knockdown in the liver, resulting in a 27% reduction in the serum LDL cholesterol level. This LNP-based all-in-one pDNA-mediated gene editing strategy highlights its potential as an oral therapeutic approach for hypercholesterolemia, opening up new possibilities for DNA-based gene medicine applications.
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Edição de Genes , Lipídeos , Fígado , Nanopartículas , Animais , Edição de Genes/métodos , Fígado/metabolismo , Nanopartículas/química , Lipídeos/química , Camundongos , Plasmídeos/genética , Plasmídeos/administração & dosagem , Técnicas de Transferência de Genes , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Humanos , DNA/administração & dosagem , DNA/genética , Duodeno/metabolismoRESUMO
Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Emerging evidence indicates that FOXO1 SNPs are related to the immune dysregulation of several autoimmune diseases suggesting that FOXO1 may be involved in inflammation and pathologic activities in patients with ITP. This study aimed to evaluate whether FOXO1 gene single-nucleotide polymorphisms (SNPs) are associated with susceptibility to ITP and clinical priorities of concern include bleeding severity and sensitivity of glucocorticoid treatment. This study recruited 327 newly diagnosed ITP and 220 healthy controls. Four SNPs (rs17446593, rs17446614, rs2721068, and rs2721068) of the FOXO1 gene were detected using the Sequenom MassArray system. Bleeding severity were classified into the mild and severe groups based on the bleeding scores. ITP patients were classified as sensitive and insensitive to glucocorticoid treatment according to the practice guideline for ITP (2019 version). The frequencies of the four SNPs did not show any significant differences between the ITP and healthy control groups. Patients with AA genotype at rs17446593 (p = 0.009) and GG genotype at rs17446614 (p = 0.009) suffered more severe bleeding than patients without them. Carriers of haplotype Grs17446593Ars17446614Crs2721068Trs2755213 were protective to severe bleeding (p = 0.002). The AA genotype at rs17446593 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment (p = 0.03). Haplotype Grs17446593Grs17446614Trs2721068Trs2755213 increases the risk of glucocorticoid resistance (p = 0.007). Although FOXO1 gene polymorphisms were not associated with susceptibility to ITP, the AA genotype at rs17446593 and GG genotype at rs17446614 were associated with bleeding severity. Haplotype GACT have a protective effect against severe bleeding. Patients with AA genotype at rs17446593 may tend to have good responds to glucocorticoid treatment. However, the FOXO1 gene haplotype GGTT increases the risk of glucocorticoid-resistant. Trial registration: ChiCTR1900022419.
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Proteína Forkhead Box O1 , Glucocorticoides , Hemorragia , Polimorfismo de Nucleotídeo Único , Púrpura Trombocitopênica Idiopática , Humanos , Glucocorticoides/uso terapêutico , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Masculino , Feminino , Criança , Proteína Forkhead Box O1/genética , Pré-Escolar , Hemorragia/genética , Haplótipos , Predisposição Genética para Doença , Estudos de Casos e Controles , Adolescente , Lactente , Índice de Gravidade de Doença , GenótipoRESUMO
Importance: Eltrombopag has been recommended for pediatric immune thrombocytopenia (ITP). Response and adverse drug reactions (ADRs) varied widely between individuals, even at the same dose of eltrombopag. The appropriate eltrombopag concentration in ITP has not been reported. Objective: This study aims to explore the appropriate eltrombopag concentration in pediatric ITP. Methods: This was a single-center, prospective cohort study. Children diagnosed with refractory persistent/chronic ITP and platelet count < 30×109/L were treated with eltrombopag and followed up for at least 2 months. Concentration was detected by high-performance liquid chromatography-mass spectrometry at least 2 weeks after eltrombopag. The clinical characteristics-concentration, concentration-response, and concentration-ADRs were analyzed. Results: A total of 30 patients were enrolled, comprising 13 males and 17 females, with a median age of 72 (45â94) months. The median dose and concentration were 1.39 (1.09â1.56) mg/kg and 2.70 (2.25â4.13) mg/L, respectively. Of the enrolled patients, 14 responded to treatment, whereas 16 did not. Additionally, five experienced adverse drug reactions. No linear correlation was observed between eltrombopag concentration and clinical characteristics. The concentration was lower in the response group than in the nonresponse group, but there was no significant difference (t = 0.755, P = 0.457). Patients who experienced ADRs had a higher concentration than those without ADRs (t = 2.538, P = 0.017). The area under the receiver operating characteristic curve of ADRs was 0.78 (95% confidence interval: 0.56â1.00). Youden's index identified the cutoff point as 4.33â¯mg/L, with a sensitivity of 88% and a specificity of 60%. Logistic regression analysis demonstrated that a higher platelet count before eltrombopag predicted a favorable response. Interpretation: Eltrombopag proves efficacious and well-tolerated for treating pediatric ITP. However, prolonged and high-dose administration may increase the likelihood of ADRs. Thus, examining the appropriate eltrombopag concentration assists in directing individualized management of pediatric ITP.
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The cornerstones of the advancement of flexible optoelectronics are the design, preparation, and utilization of novel materials with favorable mechanical and advanced optoelectronic properties. Molecular crystalline materials have emerged as a class of underexplored yet promising materials due to the reduced grain boundaries and defects anticipated to provide enhanced photoelectric characteristics. An inherent drawback that has precluded wider implementation of molecular crystals thus far, however, has been their brittleness, which renders them incapable of ensuring mechanical compliance required for even simple elastic or plastic deformation of the device. It is perplexing that despite a plethora of reports that have in the meantime become available underpinning the flexibility of molecular crystals, the "discovery" of elastically or plastically deformable crystals remains limited to cases of serendipitous and laborious trial-and-error approaches, a situation that calls for a systematic and thorough assessment of these properties and their correlation with the structure. This review provides a comprehensive and concise overview of the current understanding of the origins of crystal flexibility, the working mechanisms of deformations such as plastic and elastic bending behaviors, and insights into the examples of flexible molecular crystals, specifically concerning photoelectronic changes that occur in deformed crystals. We hope this summary will provide a reference for future experimental and computational efforts with flexible molecular crystals aimed towards improving their mechanical behavior and optoelectronic properties, ultimately intending to advance the flexible optoelectronic technology.
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Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.
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Púrpura Trombocitopênica Idiopática , Humanos , Criança , Masculino , Feminino , Estudos Retrospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/sangue , Pré-Escolar , Adolescente , Lactente , China , Doença Crônica , Resultado do Tratamento , Contagem de Plaquetas , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Hemorragia/induzido quimicamente , Receptores de Trombopoetina/agonistas , População do Leste Asiático , Tiazóis , TiofenosRESUMO
We have previously confirmed the efficacy and safety of eltrombopag (ELT) in children with chronic immune thrombocytopenia (cITP). However, data on both long-term exposure and early use of TPO-RAs are lacking, so further 'field-practice' evidence on treatment is required. Here, we report the long-term follow-up results (between September 2018 and June 2023) of our previous study. The main objective of this study was to retrospectively review our large institutional experience with ITP patients previously enrolled in our paediatric cITP study. We had more than 3 years of follow-up by June 2023 for treatment patterns and outcomes. A total of 65 patients (28 males) were enrolled, with a median age at ELT initiation of 6.34 (range 1.65, 14.13) years and a follow-up of 47.07 (36.00, 57.00) months, with 40.36 (10.53, 56.83) months of ELT therapy at the time of analysis. In total, 29.23% (19/65) of patients discontinued ELT due to stable response, and 18.46% (12/65) of patients switched to other ITP therapies due to loss of response (LOR) after 19.13 (14.53, 26.37) months. Of the 19 patients who discontinued ELT due to a stable response, 24.62% (16/65) achieved a 12 m sustained response off-treatment (SRoT); the last recorded platelet count ranged from 56 to 166 × 109 /L (median 107 × 109/L); and 4.62% (3/65) patients relapsed at 5, 6 and 9 months after discontinuation. Of the 12 patients who LOR to ELT after 19.13 (14.53, 26.37) months of therapy, four switched to avatrombopag, three switched to hetrombopag, two switched to traditional Chinese medicine (TCM), one underwent splenectomy and two received additional prednisolone under ELT treatment. Thirty-four patients who tapered and maintained a durable response. The patients with LOR and the patients with tapering were compared; the platelet count at the start of ELT is lower, and the time to response is longer in the patients with LOR. The platelet count at the start of ELT and the time to response may be the predictive factors for LOR during ELT treatment. We report more than 3 years of long-term clinical data on children with cITP using ELT. These data do not raise any new safety concerns regarding the long-term use of ELT in children with cITP.
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Púrpura Trombocitopênica Idiopática , Pirazóis , Masculino , Humanos , Criança , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Receptores de Trombopoetina , Hidrazinas/uso terapêutico , Benzoatos/uso terapêutico , ChinaRESUMO
BACKGROUND: Primary immune thrombocytopenia (ITP) in children is typically self-limiting; however, 20% to 30% of patients may experience prolonged thrombocytopenia lasting over a year. The challenge is predicting chronicity to ensure personalized treatment approaches. OBJECTIVES: To address this issue, we developed and internally validated 4 machine learning (ML) models using demographic and immunologic characteristics to predict the likelihood of chronicity. METHODS: The present study was conducted at Beijing Children's Hospital from June 2018 to December 2021, aiming to develop predictive models for determining the chronicity of pediatric ITP. Four ML models, based on a logistic regression classifier, random forest classifier, eXtreme Gradient Boosting (XGBoost), and support vector machine, were employed. These models used a set of 16 variables, including 14 immunologic and 2 demographic predictors. The performance evaluation criteria included prediction accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUROC). RESULTS: Data were collected from 662 patients who were randomly assigned to either a training dataset or a testing dataset using a random number generator. Among them, 26.5% had chronic disease. All models performed well, with AUROC values ranging from 0.81 to 0.84, and XGBoost was selected for its highest AUROC score and interpretability in constructing the predictive model. Age, T helper 17, T helper 17-to-regulatory T cell ratio, T helper 1, and double-negative T cells were identified as significant predictors by the XGBoost algorithm. CONCLUSION: We developed a precise predictive model for chronicity in pediatric ITP using ML during the initial phase. The XGBoost model achieved high predictive accuracy by using individual patient clinical parameters and demonstrated commendable interpretability.
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Púrpura Trombocitopênica Idiopática , Trombocitopenia , Criança , Humanos , Algoritmos , Área Sob a Curva , Aprendizado de Máquina , Púrpura Trombocitopênica Idiopática/diagnóstico , Trombocitopenia/diagnósticoRESUMO
Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles.
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For cell and gene therapies to become more broadly accessible, it is critical to develop and optimize non-viral cell type-preferential gene carriers such as lipid nanoparticles (LNPs). Despite the effectiveness of high throughput screening (HTS) approaches in expediting LNP discovery, they are often costly, labor-intensive, and often do not provide actionable LNP design rules that focus screening efforts on the most relevant chemical and formulation parameters. Here we employed a machine learning (ML) workflow using well-curated plasmid DNA LNP transfection datasets across six cell types to maximize chemical insights from HTS studies and has achieved predictions with 5-9% error on average depending on cell type. By applying Shapley additive explanations to our ML models, we unveiled composition-function relationships dictating cell type-preferential LNP transfection efficiency. Notably, we identified consistent LNP composition parameters that enhance in vitro transfection efficiency across diverse cell types, such as ionizable to helper lipid ratios near 1:1 or 10:1 and the incorporation of cationic/zwitterionic helper lipids. In addition, several parameters were found to modulate cell type-preferentiality, including the ionizable and helper lipid total molar percentage, N/P ratio, cholesterol to PEGylated lipid ratio, and the chemical identity of the helper lipid. This study leverages HTS of compositionally diverse LNP libraries and ML analysis to understand the interactions between lipid components in LNP formulations; and offers fundamental insights that contribute to the establishment of unique sets of LNP compositions tailored for cell type-preferential transfection.
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Improving the filtration efficiency of air filter materials is an ongoing research goal. This study conducted in-depth research on a new reduced graphene oxide air filter material, and the differences in its performance and conductivity durability before and after eliminating static electricity were tested and analyzed. The results showed that the filtration efficiency of the reduced graphene oxide air filter material significantly decreased after eliminating static electricity. The maximum decrease in filtration efficiency was observed at a filtration velocity of 0.8 m/s, with PM10 > PM1.0 > PM2.5. In this case, the filtration efficiency decreased by 11.8%, 7.98%, and 7.17%, respectively. The maximum difference in filtration efficiency of 0.29 µm particulates was about 12.7%. Eliminating static electricity slightly increased the resistance (2.5~15.5 Pa). In addition, the new reduced graphene oxide air filter material exhibited good conductivity and stability after continuous testing. This study provides data support for the application of subsequent electrification sterilization, reference values for multi-angle applications, and the development of new composite air filter materials.
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The thrombopoietin receptor agonists (TPO-RA) were recommended for primary immune thrombocytopenia (ITP) during the pandemic of COVID-19. However, the incidence of thrombocytosis and thrombosis was sporadically reported in the chronic immune thrombocytopenia (CITP) patients receiving TPO-RA during the COVID-19 infection. With the local prevalence of COVID-19 in December 2022 in the Beijing area, we got more powerful evidence about the change in platelet (Plt) counts associated with COVID-19 infection. A single-centre observational cohort study was performed from the beginning of December 2022 to the end of February 2023 to enrol CITP children treated with TPO-RA alone as the second-line treatment and suffering from the COVID-19 infection in December 2022. The Plt counts before, during and after COVID-19 infection were collected. In total, 67 (34 males and 33 females) patients with 8.10 (2.15, 15.70) years of age were enrolled. Sixty-three patients who had responded to the TPO-RA showed a transient increase in Plt counts after the infection of COVID-19. The time of starting to increase was on Day 3 (2, 7), and to the peak level on Day 14 (7, 19) of infection with the peak Plt count was 289 (88, 1974) × 109 /L. With at least 2 months observation period from COVID-19 infection, the Plt counts of 100% (63/63) patients declined to the baseline on Day 25 (14, 41). The phenomenon of transient increase in Plt counts has been shown in the CITP children who responded to TPO-RA when suffering from COVID-19 infection.
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Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by isolated thrombocytopenia and a haemorrhagic risk. Thrombopoietin receptor agonists (TPO-RAs) are highly effective for ITP and are widely used to treat patients with steroid treatment failure or dependency. However, although treatment response to TPO-RAs may differ according to the type, the potential impact of switching from eltrombopag (ELT) to avatrombopag (AVA) with respect to efficacy or tolerance in children remains unknown. This study aimed to evaluate the outcomes of switching from ELT to AVA in paediatric patients with ITP. We retrospectively evaluated children with chronic immune thrombocytopenia (cITP) switched from ELT to AVA owing to treatment failure at the Hematology-Oncology Center of Beijing Children's Hospital between July 2021 and May 2022. Overall, 11 children (seven and four boys and girls respectively) with a median age of 8.3 (range: 3.8-15.3) years were included. The overall response and complete response (platelet [PLT] count ≥100 × 109 /L) rates during AVA treatment were 81.8% (9/11) and 54.6% (6/11) respectively. The median PLT count was significantly increased from ELT to AVA (7 [range: 2-33] × 109 /L vs. 74 [15-387] × 109 /L; p = 0.007). The median time to PLT count ≥30 × 109 /L was 18 (range: 3-120) days. Overall, 7/11 patients (63.6%) used concomitant medications, and concomitant medication use was gradually discontinued within 3-6 months after AVA initiation. In conclusion, AVA after ELT is effective in the heavily pretreated paediatric cITP population, with high response rates even in those with an inadequate response to a prior TPO-RA.
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Púrpura Trombocitopênica Idiopática , Trombocitopenia , Masculino , Feminino , Humanos , Criança , Pré-Escolar , Adolescente , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Retrospectivos , Trombocitopenia/tratamento farmacológico , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Falha de Tratamento , Trombopoetina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
Eltrombopag (ELT) is effective and safe in adult persistent/chronic immune thrombocytopenia (p/cITP); a proportion could achieve a sustained response off treatment (SRoT); however, data on children are lacking. We attempted to analyse SRoT of ELT in children with p/cITP in this study. A multicentre retrospective observational study was performed in November 2022 for children with p/cITP who used ELT alone for >2 months between January 2017 and November 2021. Clinical data of pre-, during and post-ELT were collected. SRoT was defined as maintaining a platelet count of ≥30 × 109 /L without rescue therapy for at least 6 months off ELT. There were 143 patients enrolled; 69.2% (99/143) achieved an overall response of 43.3% and 25.9% achieved complete response (CR) and response (R). Among the 35 patients analysed from whom ELT was withdrawn, 71.4% (25/35) showed SRoT after discontinuing ELT without additional ITP therapy, with a median follow-up of 0.94 (range, 0.53-3.8) years, equal to 17.5% (25/143) in all patients treated with ELT. Compared with the patients with relapse (n = 10), the SRoT patients (n = 25) had a higher rate of CR (80% [20/25] vs. 40% [4/10]), shorter interval time from initiation to taper (6.4 months vs. 9.4 months), longer time from taper to withdrawal (1.1 years vs. 0.3 years) and a longer duration of ELT treatment (1.6 years vs. 0.5 years) with p < 0.05. Patients who achieved CR could attain SRoT more easily (p = 0.02). ELT had a response in 69.2% of children with p/cITP and 17.5% of them attained SRoT with good tolerance. The patients who achieved CR and began ELT treatment as early as possible, with a longer treatment duration and slower tapering, had a higher probability of SRoT.
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Púrpura Trombocitopênica Idiopática , Adulto , Humanos , Criança , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Estudos Retrospectivos , Resultado do Tratamento , Receptores de Trombopoetina , Benzoatos , Hidrazinas , ChinaRESUMO
How to build a satisfactory indoor environment has become increasingly important. In this paper, the synthesis and improvement of the most widely used polyester materials in China were carried out based on two different preparation methods, and the structures and filtration performances were tested and analyzed. The results showed that a carbon black coating was wrapped on the surfaces of the new synthetic polyester filter fibers. Compared with the original materials, the filtration efficiencies of PM10, PM2.5, and PM1 were increased by 0.88-6.26, 1.68-8.78, and 0.42-4.84%, respectively. The best filtration velocity was 1.1 m/s, and the new synthetic polyester materials with direct impregnation demonstrated superior filtration performance. The filtration efficiency of the new synthetic polyester materials was improved on the particulates with sizes of 1.0-5.0 µm. The filtration performance of G4 was better than that of G3. The filtration efficiencies of PM10, PM2.5, and PM1 were improved by 4.89, 4.20, and 11.69%, respectively. The quality factor value can be used to assess the comprehensive filtration performance of air filters in practical applications. It could provide reference values for the selection of synthetic methods of new filter materials.
RESUMO
BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases, suggesting that HIF1α may be involved in immune dysregulation in patients with immune thrombocytopenia (ITP). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to ITP and its clinical prognosis including incidence of chronic ITP and glucocorticoid sensitivity. MATERIALS AND METHODS: This study involved 197 Chinese ITP pediatric patients (discovery cohort) and 220 healthy controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect 3 SNPs genotypes in the HIF1A gene: rs11549465, rs1957757, and rs2057482. We also used another ITP cohort (N=127) to validate the significant results of SNPs found in the discovery cohort. RESULTS: The frequencies of the three SNPs did not show any significant differences between the ITP and healthy control groups. The CT genotype at rs11549465 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment ( P =0.025). These results were validated using another ITP cohort (N=127, P =0.033). Moreover, the CC genotype was a risk factor for insensitive to GT the odds ratio (95% confidence interval) was 5.96 (5.23-6.69) in standard prednisone ( P =0.0069) and 6.35 (5.33-7.37) in high-dose dexamethasone ( P =0.04). CONCLUSIONS: Although HIF1A gene polymorphisms were not associated with susceptibility to ITP, the CT genotype at rs11549465 was associated with the sensitivity to glucocorticoid treatment of ITP patients, suggesting that the rs11549465 SNP may contribute to the sensitivity of glucocorticoid treatment in pediatric ITP patients.
Assuntos
Glucocorticoides , Subunidade alfa do Fator 1 Induzível por Hipóxia , Púrpura Trombocitopênica Idiopática , Criança , Humanos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Glucocorticoides/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Anti-glycoprotein autoantibodies play a key role in the pathophysiology of ITP, but the relationship between platelet-specific antibodies and bleeding severity is unclear. This study aimed to analyze the relationship between anti-glycoprotein autoantibodies and bleeding severity in children with newly diagnosed ITP and platelet count less than 10 × 109 /L. METHOD: This was a single-center prospective observational study that analyzed children with newly diagnosed ITP and platelet count less than 10 × 109 /L between June 2018 and September 2021 at our hospital. The children were classified into the mild and severe groups based on the bleeding scores. The type and titer of anti-glycoprotein autoantibodies were detected using an enzyme-linked immunosorbent assay (ELISA) kit (PAKAUTO). We analyzed the relationship between bleeding severity and anti-glycoprotein autoantibodies. RESULTS: A total of 86 cases were enrolled, including 42 in the mild group and 44 in the severe group. Patients with anti-GPIIb/IIIa or anti-GPIb/IX antibodies suffered more severe bleeding than patients without them (χ2 = 7.303, p = .007; χ2 = 3.875, p = .049), but there was no significant difference between patients with or without anti-GPIa/IIa antibodies (χ2 = 0.745, p = .388). When antibodies were analyzed together, patients with three antibodies suffered more severe bleeding than those without three antibodies (χ2 = 5.053, p = .025). Patients with higher antibody titer in the eluent, but not in the plasma, suffered more severe bleeding in all three antibodies (Z = -2.389, p = .017; Z = -2.108, p = .035; Z = -2.557, p = .011). CONCLUSION: Anti-glycoprotein autoantibodies led to more severe bleeding in children under 18 years of age without drug treatment with newly diagnosed ITP and platelet count less than 10 × 109 /L.
Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Criança , Adolescente , Autoanticorpos , Contagem de Plaquetas , Complexo Glicoproteico GPIb-IX de Plaquetas , PlaquetasRESUMO
With the increasing popularity of fresh-air filtration systems, the methods of determining the outdoor PM2.5 design concentration have become more important. However, the monitoring of atmospheric fine particles in China started relatively late, and there are relatively few cities with complete data, with obvious regional differences, which led to many problems in the selection of air filters for fresh-air filtration systems. In this paper, three methods of determining outdoor PM2.5 design concentration were analyzed using the daily average concentration of PM2.5 in 31 provincial capital cities from 2016 to 2020. Six typical cities in different regions were also taken as examples. The advantages and disadvantages of the three existing statistical methods were compared and analyzed, as well as the corresponding differences in the selection of outdoor PM2.5 concentration value on the filter systems. The results showed that the method of mathematical induction was more accurate and reasonable for the calculation of outdoor PM2.5 design concentrations. The local outdoor PM2.5 design concentration could be quickly calculated using the recommended coefficient K and annual average PM2.5 concentration of the region, especially for small and medium-sized cities without monitoring data. However, the recommended coefficient K should be provided based on the specific region, and should be divided into values for strict conditions and normal conditions during use. This would provide a simple and effective way to select the correct air filters for practical engineering.