Clinical and genetic analysis of macrophage activation syndrome complicating juvenile idiopathic inflammatory myopathies.

BACKGROUND: Macrophage activation syndrome (MAS) is a serve complication of juvenile idiopathic inflammatory myopathies (JIIMs). This study delineates the clinical manifestations and genetic underpinnings of JIIM-MAS patients. METHODS: We retrospectively analysed clinical and UNC13D gene from JIIM patients admitted to our centre between 2011 and 2021 to identify cases of MAS. Additionally, a literature review summarising reported cases of JIIMs and MAS was performed. RESULTS: Of 773 JIIM patients, 10 (1.3%) were diagnosed with MAS. All patients presented with persistent fever and hyperferritinaemia. Seventy percent of patients met the HLH-2004 criteria, while 90% met the 2016 sJIA-MAS criteria. Most patients received combined treatment of corticosteroids and immunosuppressants. UNC13D gene analysis was performed in six patients. A homozygous pathogenic mutation (c.2588G>A) was detected in one patient with recurrent MAS, and twenty-eight single-nucleotide polymorphisms (SNPs) were detected. Eighty percent of patients exhibiting a consistent combination of ten SNPs compared to JIIM patients without MAS (35%). CONCLUSION: MAS is an early and often overlooked complication of JIIMs. The 2016 sJIA-MAS criteria may facilitate early diagnosis. Combined corticosteroid and immunosuppressant therapy prove effective. An increased prevalence of UNC13D gene polymorphisms was observed in JIIM-MAS patients, highlighting the necessity for further investigations. IMPACT: This study aimed to delineate the clinical manifestations and genetic underpinnings of macrophage activation syndrome (MAS) in ten patients with juvenile idiopathic inflammatory myopathies (JIIMs). MAS has been recognised as a complication of JIIMs. However, only a few case reports provide comprehensive descriptions of MAS in JIIM patients, and there are few reports related to UNC13D mutations in these patients. This article offers single-centre clinical insights to enhance the identification and management of MAS in JIIM patients, while also highlighting the potential association between MAS occurrence and UNC13D gene polymorphisms.

The causal relationship between gut microbiota and constipation: a two-sample Mendelian randomization study.

BACKGROUND: Constipation is one of the most common gastrointestinal disorders afflicting the population, with recent observational studies implicating dysfunction of the gut microbiota in constipation. Despite observational studies indicating a relationship, a clear causality remains unclear. This study aims to use two-sample Mendelian randomization (MR) to establish a clearer causal relationship between the two. METHODS: A two-sample Mendelian randomization (MR) study was performed using the gut microbiota summary Genome-Wide Association Studies (GWAS) statistics from MiBioGen consortium (n = 13,266) and constipation GWAS summary statistics from the IEU OpenGWAS database. The causality between gut microbiota and constipation is primarily analyzed using the inverse-variance weighted (IVW) method and reinforced by an additional four methods, including MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. Finally, funnel plot, heterogeneity test, horizontal pleiotropy test, and leave-one-out test were used to evaluate the reliability of MR results. RESULTS: IVW estimates suggested that the bacterial species Anaerotruncus, Butyricimonas, and Hungatella were causally associated with constipation. The odds ratio (OR) values of Anaerotruncus, Butyricimonas, and Hungatella were 1.08 (95% CI = 1.02-1.13; P = 0.007), 1.07 (95% CI = 1.01-1.13; P = 0.015), 1.03 (95% CI = 1.00-1.06; P = 0.037) respectively. Meanwhile, Ruminiclostridium 9 and Intestinibacter have been shown to be associated with a reduced risk of constipation. The OR of Ruminiclostridium 9 = 0.75(95% CI = 0.73-0.78, P < 0.001 and Intestinibacter of OR = 0.89 (95% CI = 0.86-0.93, P < 0.001). Furthermore, validation by funnel plot, heterogeneity test, and horizontal pleiotropy test showed that MR results were reliable. CONCLUSION: This is the first Mendelian randomization study to explore the causalities between specific gut microbiota taxa and constipation, and as such may be useful in providing insights into the unclear pathology of constipation which can in turn aid in the search for prevention and treatment.

New Species and Cytotoxicity Mechanism of Halohydroxybenzonitrile Disinfection Byproducts in Drinking Water.

Recently, seven dihalohydroxybenzonitriles (diHHBNs) have been determined as concerning nitrogenous aromatic disinfection byproducts (DBPs) in drinking water. Herein, eight new monohalohydroxybenzonitriles (monoHHBNs), including 3-chloro-2-hydroxybenzonitrile, 5-chloro-2-hydroxybenzonitrile, 3-chloro-4-hydroxybenzonitrile, 3-bromo-2-hydroxybenzonitrile, 5-bromo-2-hydroxybenzonitrile, 3-bromo-4-hydroxybenzonitrile, 5-iodo-2-hydroxybenzonitrile, and 3-iodo-4-hydroxybenzonitrile, were detected and identified in drinking water for the first time. Thereafter, the relative concentration-cytotoxicity contribution of each HHBN was calculated based on the acquired occurrence level and cytotoxicity data in this study, the genome-scale cytotoxicity mechanism was explored, and a quantitative structure-activity relationship (QSAR) model was developed. Results indicated that new monoHHBNs were present in drinking water at concentrations of 0.04-1.83 ng/L and exhibited higher cytotoxicity than some other monohalogenated aromatic DBPs. Notably, monoHHBNs showed concentration-cytotoxicity contribution comparable to diHHBNs, which have been previously identified as potential toxicity drivers in drinking water. Transcriptomic analysis revealed immunotoxicity and genotoxicity as dominant cytotoxicity mechanisms for HHBNs in Chinese hamster ovary (CHO-K1) cells, with potential carcinogenic effects. The QSAR model suggested oxidative stress and cellular uptake efficiency as important factors for their cytotoxicity, highlighting the importance of potential iodinated HHBNs in drinking water, such as 3,5-diiodo-2-hydroxybenzonitrile, for future studies. These findings are meaningful for better understanding the health risk and toxicological significance of HHBNs in drinking water.

Identification and validation of a novel 9-gene signature of non-specific classification to predict prognosis in glioma patients.

This study aimed to identify and validate a 9-gene signature for predicting overall survival (OS) in glioma patients. Analysis of multiple gene expression datasets led to the identification of 135 candidate genes associated with OS in glioma patients. Further analysis revealed that IGFBP2, PBK, NRXN3, TGIF1, DNAJA4, and LGALS3BP were identified as risk factors for OS, while ENAH, PPP2R2C, and SPHKAP were found to be protective factors. Multifaceted validation using different databases confirmed their differential expression patterns in glioma tissues compared to normal brain tissue. By utilizing LASSO regression and multivariate Cox regression analysis, a risk score was developed based on the expression levels of the 9 crucial genes. The risk score showed a significant correlation with OS in both training and validation cohorts and yielded superior predictive accuracy compared to individual gene expression. Moreover, a predictive nomogram incorporating the risk score, WHO grade, age, IDH mutation, and 1p/19q co-deletion was constructed and validated, which exhibited high predictive capabilities for survival rates at different time points. Enrichment analysis revealed the involvement of extracellular matrix-related pathways and immune system signaling in glioma prognosis. Furthermore, the risk score showed a strong correlation with immune cell infiltration and immune checkpoint expression, suggesting its potential role in the tumor immune microenvironment. In conclusion, our study provides a robust 9-gene signature and a predictive nomogram for evaluating the prognosis of glioma patients, offering valuable insights into personalized treatment strategies.

Dysfunctional phenotype of systemic and pulmonary regulatory T cells associate with lethal COVID-19 cases.

Severe cases of COVID-19 present hyperinflammatory condition that can be fatal. Little is known about the role of regulatory responses in SARS-CoV-2 infection. In this study, we evaluated the phenotype of regulatory T cells in the blood (peripheral blood mononuclear cell) and the lungs (broncho-alveolar) of adult patients with severe COVID-19 under invasive mechanical ventilation. Our results show important dynamic variation on Treg cells phenotype during COVID-19 with changes in number and functional parameters from the day of intubation (Day 1 of intensive care unit admission) to Day 7. We observed that compared with surviving patients, non-survivors presented lower numbers of Treg cells in the blood. In addition, lung Tregs of non-survivors also displayed higher PD1 and lower FOXP3 expressions suggesting dysfunctional phenotype. Further signs of Treg dysregulation were observed in non-survivors such as limited production of IL-10 in the lungs and higher production of IL-17A in the blood and in the lungs, which were associated with increased PD1 expression. These findings were also associated with lower pulmonary levels of Treg-stimulating factors like TNF and IL-2. Tregs in the blood and lungs are profoundly dysfunctional in non-surviving COVID-19 patients.

Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways.

BACKGROUND: Glabridin (Glab) is a bioactive component of licorice that can ameliorate diabetes, but its role in diabetic nephropathy (DN) has seldom been reported. Herein, we explored the effect and underlying mechanism of Glab on DN. METHODS: The bioactive component-target network of licorice against DN was by a network pharmacology approach. The protective effect of Glab on the kidney was investigated by a high-fat diet with streptozotocin induced-diabetic rat model. High glucose-induced NRK-52E cells were used for in vitro studies. The effects of Glab on ferroptosis and VEGF/Akt/ERK pathways in DN were investigated in vivo and in vitro using qRT-PCR, WB, and IHC experiments. RESULTS: Bioinformatics analysis constructed a network comprising of 10 bioactive components of licorice and 40 targets for DN. 13 matching targets of Glab were mainly involved in the VEGF signaling pathway. Glab treatment ameliorated general states and reduced FBG, HOMA-ß, and HOMA-insulin index of diabetic rats. The renal pathological changes and the impaired renal function (the increased levels of Scr, BUN, UREA, KIM-1, NGAL, and TIMP-1) were also improved by Glab. Moreover, Glab repressed ferroptosis by increasing SOD and GSH activity, and GPX4, SLC7A11, and SLC3A2 expression, and decreasing MDA and iron concentrations, and TFR1 expression, in vivo and in vitro. Mechanically, Glab significantly suppressed VEGF, p-AKT, p-ERK1/2 expression in both diabetic rats and HG-induced NRK-52E cells. CONCLUSIONS: This study revealed protective effects of Glab on the kidney of diabetic rats, which might exert by suppressing ferroptosis and the VEGF/Akt/ERK pathway.

Gastrodin suppresses pyroptosis and exerts neuroprotective effect in traumatic brain injury model by inhibiting NLRP3 inflammasome signaling pathway.

Traumatic brain injury (TBI), also known as head injury or brain injury, refers to the head injury caused by mechanical impact. It is necessary to develop effective new therapies for TBI injury. Gastrodin (GAS) is the main bioactive ingredient from the rhizome of Gastrodia elata and has significant therapeutic effect on nervous system diseases. However, the protective effects of GAS on brain tissue and related regulatory mechanism in traumatic brain injury remain elusive. Herein, we explored the role of GAS in traumatic brain injury and its related mechanism. We found Gastrodin reduced brain tissue injury and improved functional recovery of injury nerve in TBI rats, and alleviated inflammation. Gastrodin decreased the level of pyroptosis in brain tissue of TBI rats. Further, we found GAS suppressed NLRP3 inflammasome signaling pathway, and therefore suppressed pyroptosis and exerted neuroprotective effect. GAS could serve as a promising drug for TBI treatment.

Cationic Glycopolymers with Aggregation-Induced Emission for the Killing, Imaging, and Detection of Bacteria.

Cationic glycopolymers with structures similar to those of typical poly(ionic liquid)s (PILs) were synthesized via the quaternization reaction of poly(4-vinyl pyridine) with halogen-functionalized d-mannose and tetraphenylethylene units. Such postpolymerization modification provided PILs with aggregation-induced emission effect as well as specific carbohydrate-protein recognition with lectins such as concanavalin A. The interactions between cationic glycopolymers and different microorganisms, including Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, were used for the killing, imaging, and detection of bacteria. Besides, these sugar-containing PILs showed a relatively low hemolysis rate due to the presence of saccharide units, which may have potential application in the field of biomaterials.

Augmented Zika and Dengue Neutralizing Antibodies Are Associated With Guillain-Barré Syndrome.

The role of neutralizing antibodies in Zika-induced Guillain-Barré syndrome (GBS) has not yet been investigated. We conducted a case-control study using sera from the 2016 Zika epidemic in Colombia to determine the neutralizing antibody activity against Zika virus (ZIKV) and dengue virus serotype 2 (DENV2). We observed increased neutralizing antibody titers against DENV2 in ZIKV-infected individuals compared with uninfected controls and higher titers to both ZIKV and DENV2 in ZIKV-infected patients diagnosed with GBS compared with non-GBS ZIKV-infected controls. These data suggest that high neutralizing antibody titers to DENV and to ZIKV are associated with GBS during ZIKV infection.

Fidelity of a PDX-CR model for bladder cancer.

Patient-derived xenografts (PDXs) are widely recognised as a more physiologically relevant preclinical model than standard cell lines, but are expensive and low throughput, have low engraftment rate and take a long time to develop. Our newly developed conditional reprogramming (CR) technology addresses many PDX drawbacks, but lacks many in vivo factors. Here we determined whether PDXs and CRCs of the same cancer origin maintain the biological fidelity and complement each for translational research and drug development. Four CRC lines were generated from bladder cancer PDXs. Short tandem repeat (STR) analyses revealed that CRCs and their corresponding parental PDXs shared the same STRs, suggesting common cancer origins. CRCs and their corresponding parental PDXs contained the same genetic alterations. Importantly, CRCs retained the same drug sensitivity with the corresponding downstream signalling activity as their corresponding parental PDXs. This suggests that CRCs and PDXs can complement each other, and that CRCs can be used for in vitro fast, high throughput and low cost screening while PDXs can be used for in vivo validation and study of the in vivo factors during translational research and drug development.

Cornuside inhibits mast cell-mediated allergic response by down-regulating MAPK and NF-κB signaling pathways.

AIMS: The present study is to investigate the effect of cornuside on mast cell-mediated allergic response, as well as its possible mechanisms of action. METHODS: To test the anti-allergic effects of cornuside in vivo, local extravasation was induced by local injection of anti-dinitrophenyl immunoglobulin E (IgE) followed by intravenous antigenic challenge in passive cutaneous anaphylaxis model rats. Mast cell viability was determined using MTT assay. Histamine content from rat peritoneal mast cells was measured by the radioenzymatic method. To investigate the mechanisms by which cornuside affects the reduction of histamine release, the levels of calcium uptake were measured. To examine whether cornuside affects the expression of pro-inflammatory cytokines, Western blotting and ELISA were carried out. RESULTS: Oral administration of cornuside inhibited passive cutaneous anaphylaxis in rats. Presence of cornuside attenuated IgE-induced histamine release from rat peritoneal mast cells. The inhibitory effect of cornuside on histamine release was mediated by the modulation of intracellular calcium. In addition, cornuside decreased phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated production and secretion of pro-inflammatory cytokines such as TNF-α and IL-6 in human mast cells. The inhibitory effect of cornuside on pro-inflammatory cytokines was dependent on nuclear factor-κB and p38 mitogen-activated protein kinase. CONCLUSIONS: The present study provides evidence that cornuside inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. Furthermore, in vivo and in vitro anti-allergic effects of cornuside suggest a possible therapeutic application of this agent in inflammatory allergic diseases.

Low-/Negative-Pressure Hydrocephalus: To Understand the Formation Mechanism from the Perspective of Clinicians.

Low-/negative-pressure hydrocephalus (LPH/NePH) is uncommon in clinical practice, and doctors are unfamiliar with it. LPH/NePH is frequently caused by other central nervous system diseases, and patients are frequently misdiagnosed with other types of hydrocephalus, resulting in delayed treatment. LPH/NePH therapy evolved to therapeutic measures based on "external ventricular drainage below atmospheric pressure" as the number of patients with LPH/NePH described in the literature has increased. However, the mechanism of LPH/NePH formation is unknown. Thus, understanding the process of LPH/NePH development is the most important step in improving diagnosis and treatment capability. Based on case reports of LPH/NePH, we reviewed theories of transcortical pressure difference, excessive cerebral venous drainage, brain viscoelastic changes, and porous elastic sponges.

Highly effective strategy for isolation of mononuclear cells from frozen cord blood.

BACKGROUND AIMS: Cord blood mononuclear cells (CBMCs) comprise a variety of single-nucleated cells found in the cord blood, mainly consisting of monocytes and lymphocytes. They also include a smaller proportion of other cell types, such as hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). CBMCs are vital for acquiring HSPCs, MSCs, and other immune cells, like natural killer cells. These cells are essential for supporting subsequent research and clinical applications. Although automated equipment for CBMC enrichment has shown promise, the high cost of these machines and the expense of disposable consumables limit their routine use. Furthermore, limited information is available on manual strategies for isolating CBMCs from cryopreserved cord blood. Therefore, we aimed to optimize the dilution buffer and refine the isolation procedure for CBMCs. METHODS: We enhanced the CBMC recovery rate from cryopreserved cord blood using an optimized dilution buffer and a modified isolation procedure. RESULTS: We achieved average recovery rates of 42.4 % and 54.3 % for CBMCs and CD34+ cells, respectively. Notably, all reagents used in the isolation procedure were of GMP-grade or pharmaceutical preparations, underscoring the potential clinical benefits of our strategy. DISCUSSION: We devised an optimized protocol suitable for routine research and clinical applications for enhanced recovery of CBMCs from cryopreserved cord blood units using an optimized dilution buffer and a modified isolation procedure.

SP140 inhibitor suppressing TRIM22 expression regulates glioma progress through PI3K/AKT signaling pathway.

BACKGROUND: SP gene family, consisting of SP100, SP110, SP140, and SP140L, has been implicated in the initiation and advancement of numerous malignancies. Nevertheless, their clinical significance in glioma remains incompletely understood. METHOD: Expression levels and prognostic significance of SP family members were evaluated in the TCGA and CGGA datasets. Multifactorial analysis was used to identify SP gene family members that can independently impact the prognosis of glioma patients. A SP140-based predictive risk model/nomogram was developed in TCGA dataset and validated in CGGA dataset. The model's performance was evaluated through receiver operating characteristic (ROC) curves, calibration plots, and decision curve analyses. Phenotypic associations of SP140 and TRIM22 were examined through CancerSEA and TIMER. The effect of SP140 inhibitor in glioma progress and TRIM22/PI3K/AKT signaling pathway was confirmed in U251/U87 glioma cells. RESULTS: The SP family members exhibited elevated expression in gliomas and were negatively correlated with prognosis. SP140 emerged as an independent prognostic factor, and a SP140-based nomogram/predictive risk model demonstrated high accuracy. SP140 inhibitor, GSK761, lead to the suppression of TRIM22 expression and the PI3K/AKT signaling pathway. GSK761 also restrain glioma proliferation, migration, and invasion. Furthermore, SP140 and TRIM22 coexpressed in glioma cells with high level of vascular proliferation, TRIM22 is closely associated with the immune cell infiltration. CONCLUSION: SP140-based nomogram proved to be a practical tool for predicting the survival of glioma patients. SP140 inhibitor could suppress glioma progress via TRIM22/PI3K/AKT signaling pathway.

Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. METHODS: Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. RESULTS: The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo. CONCLUSIONS: We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.

Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression.

BACKGROUND: Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies. METHODS: We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment. RESULTS: Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models. CONCLUSION: This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.

ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

Safety and immunogenicity of the co-administered Na-APR-1 and Na-GST-1 hookworm vaccines in school-aged children in Gabon: a randomised, controlled, observer-blind, phase 1, dose-escalation trial.

BACKGROUND: A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area. METHODS: This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 µg, 30 µg, and 100 µg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed. FINDINGS: Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 µg of the co-administered antigens (n=8 for each injection schedule), 30 µg (n=8 for each schedule), 100 µg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively). INTERPRETATION: Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas. FUNDING: European Union Seventh Framework Programme.

Synthetic glycopolypeptides as potential inhibitory agents for dendritic cells and HIV-1 trafficking.

Multivalent binding is a key for many critical biological processes and unique recognition and specificity in binding enables many of different glycans and proteins to work in a great harmony within the human body. In this study, the binding kinetics of synthetic glycopolypeptides to the dendritic cell lectin DC-SIGN and their inhibition potential for DC-SIGN interactions with the gp120 envelope glycoprotein of HIV-1 (gp120) are investigated.

Mechanism of new coronavirus pneumonia agreement prescription on 2019 novel coronavirus-infected pneumonia based on network pharmacology analysis and the validation.

PURPOSE: To investigate the mechanism of action underlying the effective treatment of New Coronavirus Pneumonia Agreement Prescription (NCPAP) on 2019 Novel Coronavirus-Infected Pneumonia (2019-NCIP) using network pharmacology. METHODS: In this retrospective study, 50 patients with 2019-NCIP were recruited, including 16 who received symptomatic treatment and 34 that received NCPAP formula treatment on the basis of symptomatic treatment. Hospitalization and lymphocyte percentages were served as efficacy evaluation indicators. Moreover, pharmacological analysis was performed to identify the target disease of NCPAP. Active ingredients in herbs were screened using the Traditional Chinese Medications Systems Pharmacology (TCMSP) database, and related target genes were identified. We then queried therapeutic target data for coronavirus-associated genes. The protein-protein interaction network was constructed to examine the relationships between these targets. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) network enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. RESULTS: NCPAP significantly reduced hospitalization time and increased both the absolute value and percentage of lymphocytes. Bioinformatics and cytokine analysis suggested that preventing cytokine storm syndrome and regulating immune response are the key mechanisms of NCPAP in treating 2019-NCIP. CONCLUSIONS: The possible mechanisms of NCPAP in the treatment of 2019-NCIP are reduction of cytokine storms and regulation of the immune response.