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Background This study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH). Methods Eleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed. Results In group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2–2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up. Conclusion Ruxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

Recent evidence highlights the role of adiponectin in the pathophysiology of autism spectrum disorder (ASD), yielding conflicting results. The aims of this study were (1) To assess the adiponectin levels of children with ASD and typical developing (TP); (2) To investigate the relationship between adiponectin levels and symptom severity of children with ASD. This is a single-center cross-sectional study from China. From December 2017 to November 2019, first-diagnosis and drug-naive children with ASD were included. Same TP children who were matched with clinical groups by gender and age were included as the control group. The enzyme-linked immunosorbent assay (ELISA) kit was used to determine serum concentrations of adiponectin. We recorded 176 children (88 were ASD and 88 were TP children) and 77.3% (n = 136) were boys and the mean age was 4.3 years (standard deviations [S.D.]: 1.2). The mean (S.D.) levels of adiponectin were 9.01(2.19) and 11.55(2.32) μg/ml for those with ASD and TP subjects. The difference between those two groups was significant (t = 7.169, p

Recent studies have revealed the important role of long noncoding RNAs (lncRNAs) in heart development and pathogenesis. This study was aimed to investigate the role of NEAT1 in hypoxia-induced cardiac injury and explore its possible molecular mechanism. Real-time PCR (RT-PCR) was used to determine the relative RNA expression of NEAT1 and its potential target microRNA, miR-129-5p, in the plasma of patients with acute myocardial infarction, heart failure, and angina, as well as in H2O2-treated H9c2 cells. The role of NEAT1 overexpression or inhibition in H9c2 cell migration and proliferation was assessed by transwell assay and Edu staining, respectively. Collagen deposition and apoptosis were evaluated by Western blot detection of collagen and apoptotic proteins, including Capase3, Bax, and Bcl2. We showed that H2O2 treatment significantly decreased H9c2 cell migration and proliferation while increasing H9c2 cell apoptosis. Inhibition of NEAT1 attenuated the cell apoptosis and alleviated proliferation inhibition induced by hypoxia. Bioinformatics analysis showed that miR-129-5p was the direct target of NEAT1, which was confirmed by luciferase assay. NEAT1 upregulation aggravated apoptosis by downregulating miR-129-5p. In conclusion, we uncovered a novel NEAT1-miR-129 axis and its implication in H2O2-induced heart failure.

Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all- trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5′-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I–binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 ( TRIM25 ) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I–mediated antiviral signaling. We show that RIG-I could bind TRIM25 mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM25 transcripts. RIG-I could increase the transcriptional expression of TRIM25 by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I–induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation.

Rationale: Myelodysplastic syndrome (MDS) can be complicated with Crohn disease (CD). Irritable bowel disease (IBD) associated with MDS has already been reported in the past; however, hematopoietic stem cell transplantation (HSCT) is rarely performed. Herein, we report a case of CD with MDS for HSCT. Patient concerns: A 41-year-old man was hospitalized due to abdominal pain and intermittent fever for 40 days. Two years later, he was readmitted due to abdominal pain and diarrhea with fever for 10 days. Diagnosis: Symptoms, laboratory examinations, and imaging findings of the patient were indicative of CD complicated with MDS. Interventions: An allogeneic HSCT was performed. Outcomes: He died of severe lung infection 125 days post-transplantation. Lessons: The number of cases of CD combined with MDS remains insufficient, and no consensus opinions are available to date. Hence, HSCT is a very potential treatment method. Additional experiences are needed to determine its effectiveness.

Systemic sclerosis is a chronic multisystem autoimmune disease that is associated with polyclonal B cell hyperreactivity. The CDR3 of BCRs is the major site of antigen recognition. Therefore, we analyzed the BCR repertoire of patients with SSc. The BCR repertoires in 12 subjects including eight SSc patients and four healthy controls were characterized by high-throughput sequencing, and bioinformatics analysis were studied. The average CDR3 length in the SSc group was significantly shorter. The SSc patient displayed more diverse BCR. Moreover, SSc patients with mild skin sclerosis, anti-Scl70, interstitial lung disease or female sex were more diversified. B cells from the SSc patients showed a differential V and J gene usage. SSc patients had distinct BCR repertoires.These findings reflected the differences of BCR repertoires between SSc patients and controls. The higher-usage genes for the BCR sequence might be potential biomarkers of B cell-targeted therapies or diagnosis for SSc.

Itching is a leading symptom of eczema or dermatitis and has a great impact on patients’ lives. Previous studies on itching have focused mostly on atopic dermatitis (AD). A cross-sectional multicenter study was conducted among outpatients with eczema from 39 tertiary hospitals in mainland China from July 1 to September 30, 2014. This work elaborates on itching in different types of eczema. Itching was very common (97%, 8499/8758) in outpatients with eczema. The severity of the itch increased with age and disease duration (P P P P P

Significance DNMT3A is a critical epigenetic modifier and tumor suppressor in the hematopoietic system. This gene is frequently mutated in hematopoietic malignancies, including acute myeloid leukemia (AML), with Dnmt3a R878H being the most common mutant. By using a conditional knockin approach, this study shows that Dnmt3a R878H is sufficient to initiate AML and recapitulate human leukemic features in mice. The leukemia-initiating cells are enriched in hematopoietic stem/progenitor cells. Through gene expression profiling, DNA methylation and histone modification analysis, and functional tests on important regulators for cell proliferation and differentiation in an animal model, this study has not only discovered mTOR pathway activation as a key player in the disease mechanism but also revealed the potential therapeutic effects of mTOR inhibition on DNMT3A mutation-related leukemia.

Astemizole has gained attention as an antineoplastic drug that targets important ion channels. The present study aimed to investigate the protective effects of astemizole against hydrogen peroxide (H2O2)‑induced oxidative damage to human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated with astemizole (0.5 and 1 µM) for 12 h, then exposed to H2O2 (200 µM) for 12 h. Cell viability was measured using the MTT assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH‑Px), reactive oxygen species (ROS) and apoptotic percentage were determined. Additionally, the protein expression of p53, p21Cip1/Waf1 and p16INK4a was measured by western blot analysis The results demonstrated that astemizole (0.5‑1 µM) was able to significantly restore the viability of HUVECs under oxidative stress and scavenge intracellular ROS induced by H2O2. Astemizole also suppressed the production of lipid peroxides, such as MDA, and restored the activities of endogenous antioxidants, including SOD and GSH‑Px, indicating that cell apoptosis may be inhibited. In addition, astemizole significantly increased p53, p21Cip1/Waf1 and p16INK4a protein expression. In conclusion, astemizole effectively protected endothelial cells against oxidative stress induced by H2O2, a function that may involve ROS/p53/p21Cip1/Waf1/ p16INK4a signaling pathways. The present study therefore served as a preliminary investigation into the ROS‑protective effects of astemizole, and may pave the way for future studies into the development of this compound as a novel therapy for atherosclerosis.

A Super Tau Charm Facility (STCF) is one of the major options for the accelerator-based high energy project in China in the post-BEPCII era, and its R&D program is underway. The proposed STCF will span center of mass energies (√(s)) ranging from 2 to 7 GeV with a peaking luminosity above 0.5× 1035 cm−2 s−1 at √(s)=4.0 GeV, and will provide a unique platform for tau-charm physics and hadron physics. In order to evaluate the physical potential capabilities and optimize the detector design, a fast simulation package has been developed. This package takes as inputs the response of physical objects in each sub-system of the detector including resolution, efficiency as well as related variables for the kinematic fit and the secondary vertex reconstruction algorithm. It can flexibly adjust the responses of each sub-detector system and is a critical tool for the STCF R&D program.

Soluble amyloid-β (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), are thought to be the key pathogenic factor in Alzheimer's disease (AD), but there is still no effective treatment for preventing or reversing the progression of the disease. Targeting NMDA receptor trafficking and regulation is a new strategy for early treatment of AD. Aβ oligomers have been found to bind to the fibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation, thereby impairing the normal functioning of NMDA receptors and resulting in cognitive deficits. Here, we identified for the first time the interaction sites of the EphB2 FN domain with ADDLs by applying the peptide array method to design and synthesize four candidate peptides (Pep21, Pep25, Pep32, and Pep63) that might be able to block the EphB2–ADDL interaction. Among them, Pep63 was found to be the most effective at inhibiting the binding between EphB2 and ADDLs. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2- and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice and the phosphorylation and surface expression of GluN2B-containing NMDA receptors in cultures. Together, these results suggest that blocking the EphB2–ADDL interaction by small interfering peptides may be a promising strategy for AD treatment.SIGNIFICANCE STATEMENTAlzheimer's disease (AD) is an age-dependent neurodegenerative disorder and amyloid β-derived diffusible ligands (ADDLs) play a key role in triggering the early cognitive deficits that constitute AD. ADDLs may bind EphB2 and alter NMDA receptor trafficking and synaptic plasticity. Here, we identified the interaction sites of the EphB2 FN domain with ADDLs for the first time to develop a small (10 aa) peptide (Pep63) capable of blocking the EphB2–ADDL interaction. We found that Pep63 not only rescued the ADDL-induced depletion of EphB2 and GluN2B-containing NMDA receptors from the neuronal surface in cultured hippocampal neurons, but also improved impaired memory deficits in APPswe/PS1dE9 (APP/PS1) transgenic mice. Our results suggest that blocking the EphB2–ADDL interaction with Pep63 may be a promising strategy for AD treatment.

Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer’s disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer’s disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development.

Rationale In the course of endocarditis, the development of antineutrophil cytoplasmic antibody (ANCA)-mediated disease introduces the dilemma of determining the best treatment approach for immune conditions, whether immunosuppressant therapy should be added to antibiotic treatment has remained controversial. Patient concerns A 33-year-old man presented with progressive fever lasting for 7 months, and swelling, pain, and purpura in the arms and legs. The patient showed multiple autoantibodies including cytoplasmic ANCA, antiproteinase 3, rheumatoid factor, and anti-beta 2 glycoprotein I. Blood culture was positive for viridans streptococcus, and renal biopsy revealed glomerulonephritis and interstitial nephritis. Diagnosis Endocarditis caused by viridans streptococci, ANCA-associated vasculitis, and congenital ventricular septal defect. Interventions In addition to effective antibiotics, he also received twice intravenous corticosteroids and intravenous immunoglobulin therapy, and a low dose of cyclophosphamide. At last, the patient received congenital ventricular septal defect repair and debridement. Outcomes The abnormal clinical manifestations, including renal failure and loss of strength, recovered rapidly with corticosteroid therapy in addition to antibiotic treatment. After 6 months without any medications, he remained asymptomatic and was able to live normally. Lessons In this case with endocarditis and ANCA-associated vasculitis, we highlighted the importance of biopsy and immunosuppressive therapy. Histopathologic examination is required for diagnosis and treatment in such case. Identifying patients who have endocarditis and ANCA positivity with vasculitis pathologic features will require corticosteroid/immunosuppressives in addition to the antibiotics therapy.

Background DNMT3A R882H, a frequent mutation in acute myeloid leukemia (AML), plays a critical role in malignant hematopoiesis. Recent findings suggest that DNMT3A mutant acts as a founder mutation and requires additional genetic events to induce full-blown AML. Here, we investigated the cooperation of mutant DNMT3A and NRAS in leukemogenesis by generating a double knock-in (DKI) mouse model harboring both Dnmt3a R878H and Nras G12D mutations. Methods DKI mice with both Dnmt3a R878H and Nras G12D mutations were generated by crossing Dnmt3a R878H knock-in (KI) mice and Nras G12D KI mice. Routine blood test, flow cytometry analysis and morphological analysis were performed to determine disease phenotype. RNA-sequencing (RNA-seq), RT-PCR and Western blot were carried out to reveal the molecular mechanism. Results The DKI mice developed a more aggressive AML with a significantly shortened lifespan and higher percentage of blast cells compared with KI mice expressing Dnmt3a or Nras mutation alone. RNA-seq analysis showed that Dnmt3a and Nras mutations collaboratively caused abnormal expression of a series of genes related to differentiation arrest and growth advantage. Myc transcription factor and its target genes related to proliferation and apoptosis were up-regulated, thus contributing to promote the process of leukemogenesis. Conclusion This study showed that cooperation of DNMT3A mutation and NRAS mutation could promote the onset of AML by synergistically disturbing the transcriptional profiling with Myc pathway involvement in DKI mice.

To examine whether plasma fatty acid-binding protein 4 concentrations, measured in the first trimester, are associated with gestational diabetes mellitus (GDM).This prospective, multicenter cohort study was conducted at three maternity centers in two cities (Harbin and Beijing) in China from July 2015 to June 2016. Data for fasting plasma glucose and fatty acid-binding protein 4 concentrations in the first trimester and one-step GDM screening with a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation were collected and analyzed.Plasma from women in the first trimester was available for 1,150 women, of whom 135 (11.7%) developed GDM. The GDM distribution across the fatty acid-binding protein 4 quartiles ranged from 3.8% (first quartile) to 21.6% (fourth quartile). In multivariate models comparing the second (quartile 2), third, and fourth quartiles against the first quartile of fatty acid-binding protein 4, concentrations of fatty acid-binding protein 4 in quartile 2, quartile 3, and quartile 4 were associated with the development of GDM with respective associated adjusted odds ratios (95% CIs) of 1.76 (1.21-2.58), 2.36 (1.55-4.29), and 3.57 (1.99-6.11). A significant difference in the area under receiver operating characteristic curve between established risk factors alone and the addition of fatty acid-binding protein 4 concentrations was observed (difference 0.042 [95% CI 0.028-0.055]; P=.03).Higher fatty acid-binding protein 4 concentrations in the first trimester visit were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies.

Little is known about the classification and bacterial infection in outpatients with eczema and dermatitis in China.To investigate the prevalence of eczema and dermatitis in outpatients of dermatology clinics in China, examine classification and proportion of common types of dermatitis and the possible bacterial infection, and analyze the possible related factors.Outpatients with eczema or dermatitis from 39 tertiary hospitals of 15 provinces in mainland China from July 1 to September 30, 2014, were enrolled in this cross-sectional and multicenter study. Among 9393 enrolled outpatients, 636 patients (6.7%) were excluded because of incomplete information.The leading subtypes of dermatitis were unclassified eczema (35.5%), atopic dermatitis (13.4%), irritant dermatitis (9.2%), and widespread eczema (8.7%). Total bacterial infection rate was 52.3%, with widespread eczema, stasis dermatitis, and atopic dermatitis being the leading three (65.7%, 61.8%, and 61.4%, respectively). Clinically very likely bacterial infection has a significant positive correlation with disease duration, history of allergic disease, history of flexion dermatitis, and severe itching.Atopic dermatitis has become a common subtype of dermatitis in China. Secondary bacterial infection is common in all patients with dermatitis, and more attentions should be paid on this issue in other type of dermatitis apart from atopic dermatitis.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which affects more and more people. But there is still no effective treatment for preventing or reversing the progression of the disease. Soluble amyloid-beta (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs) play an important role in AD. Synaptic activity and cognition critically depend on the function of glutamate receptors. Targeting N-methyl-D-aspartic acid (NMDA) receptors trafficking and its regulation is a new strategy for AD early treatment. EphB2 is a key regulator of synaptic localization of NMDA receptors. Aβ oligomers could bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. Here we identified that overexpression of EphB2 with lentiviral vectors in dorsal hippocampus improved impaired memory deficits and anxiety or depression-like behaviors in APPswe/PS1-dE9 (APP/PS1) transgenic mice. Phosphorylation and surface expression of GluN2B-containing NMDA receptors were also improved. Overexpression of EphB2 also rescued the ADDLs-induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons. These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in hippocampus may be a promising strategy for AD treatment.

The prevalence of atopic dermatitis (AD) has increased substantially. Previous studies have focused mostly on pediatric patients, while epidemiological investigation on adult AD has been very limited. The aim of this study was to determine the prevalence and clinical features of adult AD in outpatients with dermatitis and eczema in China mainland. A multicenter cross-sectional study was conducted among outpatients with eczema or dermatitis from 39 tertiary hospitals of 15 provinces in China from July 1 to September 30, 2014. Of 8758 patients, 407 were adult AD. Compared with adults with other types of dermatitis, the mean age (41.8 ± 14.3 vs 42.04 ± 15.38 years, P 0.05). The highest (8.7%) and lowest prevalence (3.7%) of adult AD were in 25°N to 30°N and 35°N to 40°N latitude region. A substantial part of adult outpatients with eczema or dermatitis is adult AD. Middle age, more body location involvement, more suspected bacterial infection, and severe itching are the main clinical feathers of adult AD. Geographical environment and economic situation work in synergy to adult AD.