One-Pot Total Synthesis of Natural Products Nitramarine, Nitraridine, and Analogues via a Cascade Oxidation/Pictet-Spengler Condensation/Annulation Process.

A cascade oxidation/Pictet-Spengler condensation/annulation process has been developed for the one-pot total synthesis of nitramarine, nitraridine, and their analogues. The procedure proceeded with easily available quinolines and tryptophan derivatives. A simple and metal-free approach, wide substrate scope, and functional group tolerance make it applicable for the synthesis of diverse bioactive nitramarine, nitraridine, and their derivatives. Furthermore, the bioactivity evaluation has identified two promising leading compounds 5d and 5e with potent antitumor proliferative activity against breast cancer cells.

Andrographolide suppresses breast cancer progression by modulating tumor-associated macrophage polarization through the Wnt/ß-catenin pathway.

Andrographolide(ADE) has been demonstrated to inhibit tumor growth through direct cytotoxicity on tumor cells. However, its potential activity on tumor microenvironment (TME) remains unclear. Tumor-associated macrophages (TAMs), composed mainly of M2 macrophages, are the key cells that create an immunosuppressive TME by secretion of cytokines, thus enhancing tumor progression. Re-polarized subpopulations of macrophages may represent vital new therapeutic alternatives. Our previous studies showed that ADE possessed anti-metastasis and anoikis-sensitization effects. Here, we demonstrated that ADE significantly suppressed M2-like polarization and enhanced M1-like polarization of macrophages. Moreover, ADE inhibited the migration of M2 and tube formation in HUVECs under M2 stimulation. In vivo studies showed that ADE restrained the growth of MDA-MB-231 and HCC1806 human breast tumor xenografts and 4T-1 mammary gland tumors through TAMs. Wnt5a/ß-catenin pathway and MMPs were particularly associated with ADE's regulatory mechanisms to M2 according to RNA-seq and bioinformatics analysis. Moreover， western blot also verified the expressions of these proteins were declined with ADE exposure. Among the cytokines released by M2, PDGF-AA and CCL2 were reduced. Our current findings for the first time elucidated that ADE could modulate macrophage polarization and function through Wnt5a signaling pathway, thereby playing its role in inhibition of triple-negative breast cancer.

Evaluation of piggyBac-mediated anti-CD19 CAR-T cells after ex vivo expansion with aAPCs or magnetic beads.

Adoptive immunotherapy is a new potential method of tumour therapy, among which anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T cell), is a typical treatment agent for haematological malignancies. Previous clinical trials showed that the quality and phenotype of CAR-T cells expanded ex vivo would seriously affect the tumour treatment efficacy. Although magnetic beads are currently widely used to expand CAR-T cells, the optimal expansion steps and methods have not been completely established. In this study, the differences between CAR-T cells expanded with anti-CD3/CD28 mAb-coated beads and those expanded with cell-based aAPCs expressing CD19/CD64/CD86/CD137L/mIL-15 counter-receptors were compared. The results showed that the number of CD19-specific CAR-T cells with a 4-1BB and CD28 co-stimulatory domain was much greater with stimulation by aAPCs than that with beads. In addition, the expression of memory marker CD45RO was higher, whereas expression of exhausted molecules was lower in CAR-T cells expanded with aAPCs comparing with the beads. Both CAR-T cells showed significant targeted tumoricidal effects. The CAR-T cells stimulated with aAPCs secreted apoptosis-related cytokines. Moreover, they also possessed marked anti-tumour effect on NAMALWA xenograft mouse model. The present findings provided evidence on the safety and advantage of two expansion methods for CAR-T cells genetically modified by piggyBac transposon system.

Administration of tissue plasminogen activator without coagulation results in a Chinese population.

Routine coagulation test before intravenous tissue plasminogen activator (tPA) use increases the door to needle time (DNT). We sought to evaluate the safety of tPA use without coagulation results and its impact on prognosis. In our stroke registry, tPA was delivered with coagulation results from December 2015 to April 2016 and without coagulation results from May 2016 to December 2016. Differences of demographics, clinical characteristic, and prognosis between these two groups were analyzed. In addition, logistic regression analysis was conducted to identify predictors for DNT of over 60 min. A total of 201 stroke patients were included in the final analysis. Of these, 81 patients received tPA with coagulation results and 120 patients without coagulation results. Only one (0.8%) patient with abnormal coagulation results met the exclusion criteria of tPA use in patients without coagulation results. The difference of DNT between groups with (mean, 61.7 min) and without (mean, 41.9 min) coagulation results was significant (P = 0.00). The group without coagulation results had a higher rate of favorable 90-day outcome (74.2 vs 70.4%) and lower rates of symptomatic intracranial hemorrhage/nonintracranial hemorrhage (4.9 and 22.2% vs 1.7 and 19.2%) than the group with coagulation results did; these differences were not statistically significant. In multivariate analysis, only tPA use with coagulation results was the predictor for DNT of over 60 min (P = 0.0030, OR = 2.44, 95% CI 1.28-4.65). The present study suggests that tPA could be delivered safely without coagulation results in patients without suspected coagulopathy, and avoiding coagulation tests reduces significantly the DNT interval.

Minor Nonintracranial Hemorrhage and Poor Prognosis among Stroke Patients Undergoing Intravenous Thrombolysis.

BACKGROUND: Whether nonintracranial hemorrhage (NICH) associated with intravenous thrombolysis (IVT) is a predictor of intracranial hemorrhage (ICH) and poor prognosis is ambiguous. We sought to analyze the rate of NICH and the relationship between NICH and poor outcome in the ischemic stroke population undergoing IVT. METHODS: This is a single-center, hospital-based prospective study. All ischemic stroke patients undergoing IVT between December 2015 and November 2016 were included. NICH was defined according to the criteria of the Bleeding Academic Research Consortium (BARC). ICH associated with IVT was defined based on the European Cooperative Acute Stroke Study II definition. On the basis of the modified Rankin Scale (mRS), 90-day outcome was divided into favorable outcome (mRS score 0-1) versus unfavorable outcome (mRS score 2-6) and independency (mRS score 0-2) versus dependency and death (mRS score 3-6). RESULTS: A total of 212 patients undergoing IVT were included in the analysis. Forty-five NICH events were reported in 42 patients (19.8%). Older age was independently associated with NICH (P = .049, odds ratio [OR] = .97, 95% confidence interval [CI] .94-1.0). Neither NICH with BARC class 1 or higher (P = .56, OR = .61, 95% CI .11-3.24) nor NICH with BARC class 2 or higher (P = .87, OR = 1.19, 95% CI .14-10.23) was associated with ICH. NICH with BARC class 1 or higher was not associated with unfavorable outcome (P = .67, OR = 1.17, 95% CI .56-2.45) and dependence and death (P = .47, OR = .72, 95% CI .30-1.75), neither was NICH with BARC class 2 or higher (P = .97, OR = 1.02, 95% CI .46-2.27 and P = .30, OR = .59, 95% CI .22-1.62). CONCLUSIONS: NICH was common among ischemic stroke populations receiving IVT. NICH with BARC class 2 or lower was not associated with ICH and poor outcome.

Flexible Job Shop Scheduling via Dual Attention Network-Based Reinforcement Learning.

Flexible manufacturing has given rise to complex scheduling problems such as the flexible job shop scheduling problem (FJSP). In FJSP, operations can be processed on multiple machines, leading to intricate relationships between operations and machines. Recent works have employed deep reinforcement learning (DRL) to learn priority dispatching rules (PDRs) for solving FJSP. However, the quality of solutions still has room for improvement relative to that by the exact methods such as OR-Tools. To address this issue, this article presents a novel end-to-end learning framework that weds the merits of self-attention models for deep feature extraction and DRL for scalable decision-making. The complex relationships between operations and machines are represented precisely and concisely, for which a dual-attention network (DAN) comprising several interconnected operation message attention blocks and machine message attention blocks is proposed. The DAN exploits the complicated relationships to construct production-adaptive operation and machine features to support high-quality decision-making. Experimental results using synthetic data as well as public benchmarks corroborate that the proposed approach outperforms both traditional PDRs and the state-of-the-art DRL method. Moreover, it achieves results comparable to exact methods in certain cases and demonstrates favorable generalization ability to large-scale and real-world unseen FJSP tasks.

Recycling of manganese ore desulfurization slag for preparation of low-temperature NH3-SCR catalyst with good scale-up production performance.

Considering the synergistic carbon/pollution reduction and resource utilization, this study proposes recycling of manganese desulfurization slag to prepare low-temperature NH3 -SCR catalyst based on solid-state ion-exchange. The desulfurization slag was hydrothermally treated to be support under mild conditions, with the parent manganese oxide ore serving as active component. Hydrothermal treatment with a desulfurization slag to NaOH mass ratio of 1.0, at 100 °C for 10 h were actually cost-effective conditions for DS recycling. The catalyst with 13.6 wt% of Mn and activated at 450 °C for 2 h in air (MO3/DSH-450 -2) performed the best, with a NO conversion of 86.9% at 150 °C and 10000 h-1, and up to 92.6% at 175 °C. Hydrothermal treatment of DS, SSIE and calcination activation resulting in a rich surface acidity and lattice oxygen of MO3/DSH, coupled with better chemical state distribution of active metal sites, promoting the NH3 -SCR activity. The scale-up produced MO3/DSH-G maintained 90.4% NOx conversion at 175 °C, showing good robustness, flexibility, and better sulfur/water resistance. The development of MO3/DSH catalyst may make full use of natural manganese ore, is a typical coupling strategy for carbon-pollutant synergistic emission reduction and resource fully utilize.

Transcriptome-wide analysis reveals the coregulation of RNA-binding proteins and alternative splicing genes in the development of atherosclerosis.

RNA-binding proteins (RBPs) are involved in the regulation of RNA splicing, stability, and localization. How RBPs control the development of atherosclerosis, is not fully understood. To explore the relevant RNA-binding proteins (RBPs) and alternative splicing events (ASEs) in atherosclerosis. We made a comprehensive work to integrate analyses of differentially expressed genes, including differential RBPs, and variable splicing characteristics related to different stages of atherosclerosis in dataset GSE104140. A total of 3712 differentially expressed genes (DEGs) were identified, including 2921 upregulated genes and 791 downregulated genes. Further analysis screened out 54 RBP genes, and 434 AS genes overlapped DEGs. We selected high expression ten RBP genes (SAMHD1, DDX60 L, TLR7, RBM47, MYEF2, RNASE6, PARP12, APOBEC3G, SMAD9, and RNASE1) for co-expression analysis. Meanwhile, we found seven regulated alternative splicing genes (RASGs) (ABI1, FXR1, CHID1, PLEC, PRKACB, BNIP2, PPP3CB) that could be regulated by RBPs. The co-expression network was used to further elucidate the regulatory and interaction relationship between RBPs and AS genes. Apoptotic process and innate immune response, revealed by the functional enrichment analysis of RASGs regulated by RBPs were closely related to atherosclerosis. In addition, 26 of the 344 alternative splicing genes regulated by the above 10 RBPs were transcription factors (TFs), We selected high expression nine TFs (TFDP1, RBBP7, STAT2, CREB5, ERG, ELF1, HMGN3, BCLAF1, and ZEB2) for co-expression analysis. The target genes of these TFs were mainly enriched in inflammatory and immune response pathways that were associated with atherosclerosis. indicating that AS abnormalities of these TFs may have a function in atherosclerosis. Furthermore, the expression of differentially expressed RBPs and the alternative splicing events of AS genes was validated by qRT-PCR in umbilical vein endothelial cells (HUVEC). The results showed that RBM47 were remarkedly difference in HUVEC treated with ox-LDL and the splicing ratio of AS in BCLAF1which is regulated by RBM47 significantly changed. In conclusion, the differentially expressed RBPs identified in our analysis may play important roles in the development of atherosclerosis by regulating the AS of these TF genes.

Identification and functional analysis of a novel de novo missense mutation located in the initiation codon of LAMP2 associated with early onset female Danon disease.

BACKGROUND: Danon disease is characterized by the failure of lysosomal biogenesis, maturation, and function due to a deficiency of lysosomal membrane structural protein (LAMP2). METHODS: The current report describes a female patient with a sudden syncope and hypertrophic cardiomyopathy phenotype. We identified the pathogenic mutations in patients by whole-exon sequencing, followed by a series of molecular biology and genetic approaches to identify and functional analysis of the mutations. RESULTS: Suggestive findings by cardiac magnetic resonance (CMR), electrocardiogram (ECG), and laboratory examination suggested Danon disease which was confirmed by genetic testing. The patient carried a novel de novo mutation, LAMP2 c.2T>C located at the initiation codon. The quantitative polymerase chain reaction (qPCR) and Western blot (WB) analysis of peripheral blood leukocytes from the patients revealed evidence of LAMP2 haploinsufficiency. Labeling of the new initiation codon predicted by the software with green fluorescent protein followed by fluorescence microscopy and Western blotting showed that the first ATG downstream from the original initiation codon became the new translational initiation codon. The three-dimensional structure of the mutated protein predicted by alphafold2 revealed that it consisted of only six amino acids and failed to form a functional polypeptide or protein. Overexpression of the mutated LAMP2 c.2T>C showed a loss of function of the protein, as assessed by the dual-fluorescence autophagy indicator system. The mutation was confirmed to be null, AR experiments and sequencing results confirmed that 28% of the mutant X chromosome remained active. CONCLUSION: We propose possible mechanisms of mutations associated with haploinsufficiency of LAMP2: (1) The inactivation X chromosome carrying the mutation was not significantly skewed. However, it decreased in the mRNA level and the expression ratio of the mutant transcripts; (2) The identified mutation is null, and the active mutant transcript fails to translate into the normal LAMP2 proteins. The presence of haploinsufficiency in LAMP2 and the X chromosome inactivation pattern were crucial factors contributing to the early onset of Danon disease in this female patient.

Methylation and transcriptomic expression profiles of HUVEC in the oxygen and glucose deprivation model and its clinical implications in AMI patients.

The obstructed coronary artery undergoes a series of pathological changes due to ischemic-hypoxic shocks during acute myocardial infarction (AMI). However, the altered DNA methylation levels in endothelial cells under these conditions and their implication for the etiopathology of AMI have not been investigated in detail. This study aimed to explore the relationship between DNA methylation and pathologically altered gene expression profile in human umbilical vein endothelial cells (HUVECs) subjected to oxygen-glucose deprivation (OGD), and its clinical implications in AMI patients. The Illumina Infinium MethylationEPIC BeadChip assay was used to explore the genome-wide DNA methylation profile using the Novaseq6000 platform for mRNA sequencing in 3 pairs of HUVEC-OGD and control samples. GO and KEGG pathway enrichment analyses, as well as correlation, causal inference test (CIT), and protein-protein interaction (PPI) analyses identified 22 hub genes that were validated by MethylTarget sequencing as well as qRT-PCR. ELISA was used to detect four target molecules associated with the progression of AMI. A total of 2,524 differentially expressed genes (DEGs) and 22,148 differentially methylated positions (DMPs) corresponding to 6,642 differentially methylated genes (DMGs) were screened (|Δß|>0.1 and detection p < 0.05). After GO, KEGG, correlation, CIT, and PPI analyses, 441 genes were filtered. qRT-PCR confirmed the overexpression of VEGFA, CCL2, TSP-1, SQSTM1, BCL2L11, and TIMP3 genes, and downregulation of MYC, CD44, BDNF, GNAQ, RUNX1, ETS1, NGFR, MME, SEMA6A, GNAI1, IFIT1, and MEIS1. DNA fragments BDNF_1_ (r = 0.931, p < 0.0001) and SQSTM1_2_NEW (r = 0.758, p = 0.0043) were positively correlated with the expressions of corresponding genes, and MYC_1_ (r = -0.8245, p = 0.001) was negatively correlated. Furthermore, ELISA confirmed TNFSF10 and BDNF were elevated in the peripheral blood of AMI patients (p = 0.0284 and p = 0.0142, respectively). Combined sequencing from in vitro cellular assays with clinical samples, aiming to establish the potential causal chain of the causal factor (DNA methylation) - mediator (mRNA)-cell outcome (endothelial cell ischemic-hypoxic injury)-clinical outcome (AMI), our study identified promising OGD-specific genes, which provided a solid basis for screening fundamental diagnostic and prognostic biomarkers of coronary endothelial cell injury of AMI. Moreover, it furnished the first evidence that during ischemia and hypoxia, the expression of BNDF was regulated by DNA methylation in endothelial cells and elevated in peripheral blood.

Rates of intravenous thrombolysis and endovascular therapy for acute ischaemic stroke in China between 2019 and 2020.

BACKGROUND: In recent years, a series of initiatives have been launched to promote intravenous thrombolysis (IVT) and endovascular therapy (EVT) for acute ischaemic stroke (AIS) in China. We aimed to update the rates of IVT and EVT in China between 2019 and 2020 and to evaluate the current IVT and EVT according to hospital grades. METHODS: Cross-sectional data on patients receiving IVT/EVT were derived from the Bigdata Observatory platform for Stroke of China (BOSC). The monthly number of discharged patients with a principal diagnosis of AIS was derived from the first pages of medical records of each hospital. The rates and information of IVT and EVT were analysed according to hospital grades. FINDINGS: During this period, 938 tertiary hospitals and 786 secondary hospitals from 31 provinces continuously reported data to the BOSC. The overall IVT rate for AIS was 5·64%, and the EVT rate was 1·45%. The IVT rate in secondary hospitals was higher than that in tertiary hospitals (6·39% vs. 5·39%, P < 0·001), whereas the EVT rate in secondary hospitals was much lower than that in tertiary hospitals (0·29% vs. 1·84%, P < 0·001). Significant differences in demographic and clinical characteristics of patients receiving IVT/EVT were also shown between tertiary and secondary hospitals. INTERPRETATION: The rates of IVT and EVT for AIS have greatly increased in China, but there is still a large gap compared with developed countries. Hospital inhomogeneity in IVT and EVT suggests the importance of developing a region-specific network for stroke treatment. FUNDING: None.

Efficacy of Enhanced Cytokine-Induced Killer Cells as an Adjuvant Immunotherapy for Renal Cell Carcinoma: Preclinical and Clinical Studies.

Cytokine-induced killer (CIK) cells have been proved to be an effective method of tumor immunotherapy in numerous preclinical and clinical studies. In our previous study, a new method was developed to prime and propagate CIK cells by the combination of IL-2 and IL-15, and this kind of CIK cells had enhanced antitumor effect on lung cancer. For renal cell carcinoma (RCC), immunotherapy plays an important role because of the poor efficacy of radiotherapy and chemotherapy. In this study, we further evaluated the antitumor effects of these enhanced CIK cells against RCC. Enhanced CIK cells were generated by IL-2 combined with IL-15 and identified by flow cytometry. HEK-293 and ACHN cell lines were used to verify the efficiency of CIK cells in vitro, and then the ACHN tumor xenograft model was also employed for in vivo study. In addition, the secreted cytokines including IFN-γ, granzyme B, TNF-α, and perforin, as well as the local microstructure were also studied. Subsequently, 20 patients with RCC were enrolled into our study, and 11 patients were randomly divided into the autologous CIK treatment group for clinical research. The results showed that enhanced CIK cells exert better antitumor effects in RCC in vitro (p < 0.01 in HEK-293 and p < 0.05 in ACHN）and in vivo (p < 0.05). Patients benefit overall survival from enhanced CIK therapy in our clinical study. Our present preclinical and clinical studies for the first time elucidated that these enhanced CIK cells would be used as an effective adjuvant therapy in the treatment of RCC.

Effectiveness of intravenous r-tPA versus UK for acute ischaemic stroke: a nationwide prospective Chinese registry study.

BACKGROUND: Intravenous recombinant tissue plasminogen activator (r-tPA) and urokinase (UK) are both recommended for the treatment of acute ischaemic stroke (AIS) in China, but with few comparative outcome data being available. We aimed to compare the outcomes of these two thrombolytic agents for the treatment of patients within 4.5 hours of onset of AIS in routine clinical practice in China. METHODS: A pre-planned, prospective, nationwide, multicentre, real-world registry of consecutive patients with AIS (age ≥18 years) who received r-tPA or UK within 4.5 hours of symptom onset according to local decision-making and guideline recommendations during 2017-2019. The primary effectiveness outcome was the proportion of patients with an excellent functional outcome (defined by modified Rankin scale scores 0 to 1) at 90 days. The key safety endpoint was symptomatic intracranial haemorrhage according to standard definitions. Multivariable logistic regression was used for comparative analysis, with adjustment according to propensity scores to ensure balance in baseline characteristics. RESULTS: Overall, 4130 patients with AIS were registered but 320 had incomplete or missing data, leaving 3810 with available data for analysis of whom 2666 received r-tPA (median dose 0.88 (IQR 0.78-0.90) mg/kg) and 1144 received UK (1.71 (1.43-2.00)×104 international unit per kilogram). There were several significant intergroup differences in patient characteristics: r-tPA patients were more educated, had less history of stroke, lower systolic blood pressure, greater neurological impairment and shorter treatment times from symptom onset than UK patients. However, in adjusted analysis, the frequency of excellent outcome (OR 1.18, 95% CI 1.00 to 1.40, p=0.052) and symptomatic intracranial haemorrhage (OR 0.70, 95% CI 0.33 to 1.47, p=0.344) were similar between groups. CONCLUSIONS: UK may be as effective and carry a similar safety profile as r-tPA in treating mild to moderate AIS within guidelines in China. REGISTRATION: http://www.clinicaltrials.gov. unique identifier: NCT02854592.

Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Ameliorate HaCaT Cell Photo-Aging.

Umbilical cord mesenchymal stem cells (UCMSCs) have been identified as a potentially ideal cell type for use in regenerative therapeutic contexts owing to their excellent paracrine secretory abilities and other desirable properties. Previous work has shown that stem cell-derived exosomes can effectively reduce skin aging, but few studies have specifically focused on the role of UCMSC-derived exosomes in this context. In this study, we isolated exosomes derived from UCMSCs grown in a three-dimensional culture system and explored their ability to modulate the photo-aging of HaCaT keratinocytes. Cell viability and proliferation were assessed using CCK8 assay, whereas wound healing and transwell assays were used to assess cell migratory capabilities. UVB irradiation (60 mJ/cm2) was used to induce photo-aging of HaCaT cells. TUNEL and SA-ß-Gal staining were used to explore HaCaT cell apoptosis and senescence, respectively, whereas real-time quantitative PCR was used to assess the expression of relevant genes at the mRNA level. We found that UCMSC-derived exosomes were able to enhance normal HaCaT cell proliferation and migration while also inhibiting UVB-induced damage to these cells. These exosomes also reduced HaCaT cell apoptosis and senescence, increasing collagen type I expression and reducing matrix metalloproteinase (MMP1) expression in photo-aged HaCaT cells. Together, these findings indicate that UCMSC-derived exosomes have the potential to be used therapeutically to suppress skin aging.

Biomechanical Comparison of a New Memory Compression Alloy Plate versus Traditional Titanium Plate for Anterior Cervical Discectomy and Fusion: A Finite Element Analysis.

OBJECTIVE: To compare the biomechanical properties of a new memory compression alloy plate and traditional titanium plate after anterior cervical discectomy and fusion (ACDF). METHODS: A finite element model of the C3-7 segments was developed and validated. The C5-6 disc was removed, and an intervertebral cage made of peek material was implanted. Then, a new memory compression alloy plate composed of Ti-Ni memory alloy and a traditional titanium plate were integrated at the C5-6 segment. All models were subjected to a load of 73.6 N to simulate the head weight and 1 Nm of flexion-extension, lateral bending, and axial rotation. The range of segmental motion (ROM) and stress on the prostheses, adjacent discs, and endplates were analyzed. RESULTS: Compared with intact status, ACDF with the new prothesis and traditional titanium plate reduced the ROM of C5-6 in six directions by 95.2%-100% and increased that of adjacent discs (C4-5 and C6-7) by 4.8%-112.5%. Adjacent disc stress peaks were higher for the traditional titanium plate (0.7-4.2 MPa) than for the new prosthesis (0.6-4.1 MPa). Endplate stress peaks were the highest in ACDF with the new prosthesis (15.6-53.3 MPa), followed by ACDF with traditional titanium plate (5.0-29.4 MPa). Stress peaks were significantly lower for the new prothesis (12.8-52.3 MPa) than for the traditional titanium plate (397.0-666.1 MPa). CONCLUSIONS: The new prosthesis improved the immediate stability of the surgical site and had an elastic modulus that was smaller than that of traditional titanium plate, making it conducive to reducing stress shielding and the impact on the adjacent intervertebral disc.

Therapeutic effect of transplanted umbilical cord mesenchymal stem cells in a cynomolgus monkey model of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease affecting 2.5 million young people worldwide because of its immune-mediated pathological mechanisms. Recent studies have shown that stem cell transplantation is a new potential therapy for MS. There has been renewed interest in cell therapy to improve quality of life for MS patients. In this study, the experimental autoimmune encephalomyelitis (EAE) model, which is the most commonly model to mimic MS, was successfully established in cynomolgus monkeys. To evaluate the therapeutic effect of human umbilical cord mesenchymal stem cells (UCMSCs) on MS, we intravenously transplanted UCMSCs into cynomolgus monkeys with EAE. Our results showed that UCMSC transplantation significantly ameliorated the clinical symptoms of MS. Magnetic resonance imaging and clinical signs indicated that demyelination was obviously decreased after UCMSCs therapy. Moreover, the present study showed that the mechanisms, involved in the effects of UCMSCs on MS, included their immunomodulatory functions to regulate cytokine secretion and affect functional differentiation of the T cell lineage.

Outcome of multimodal MRI-guided intravenous thrombolysis in patients with stroke with unknown time of onset.

OBJECTIVE: Intravenous tissue plasminogen activator (tPA) is the standard therapy for patients with acute ischaemic stroke (AIS) within 4.5 hours of onset. Recent trials have expanded the endovascular treatment window to 24 hours. We investigated the efficacy and safety of using multimodal MRI to guide intravenous tPA treatment for patients with AIS of unknown time of onset (UTO). METHODS: Data on patients with AIS with UTO and within 4.5 hours of onset were reviewed. Data elements collected and analysed included: demographics, National Institutes of Health Stroke Scale (NIHSS) score at baseline and 2 hours, 24 hours, 7 days after thrombolysis and before discharge, the modified Rankin Scale (mRS) score at 3 months after discharge, imaging findings and any adverse event. RESULTS: Forty-two patients with UTO and 62 in control group treated within 4.5 hours of onset were treated with intravenous tPA. The NIHSS scores after thrombolysis and/or before discharge in UTO group were significantly improved compared with the baseline (p<0.05). Between the two groups, no significant differences in NIHSS score were observed (p>0.05). Utilising the non-inferiority test, to compare mRS scores (0-2) at 3 months between the two groups, the difference was 5.2% (92% CI, OR 0.196). Patients in the UTO group had mRS scores of 0-2, which were non-inferior to the control group. Their incidence of adverse events was similar. CONCLUSIONS: Utilising multimodal MRI to guide intravenous only thrombolysis for patients with AIS with UTO was safe and effective. In those patients with AIS between 6 and 24 hours of time of onset but without large arterial occlusion, intravenous thrombolysis could be considered an option.

Network pharmacology-based identification of major component of Angelica sinensis and its action mechanism for the treatment of acute myocardial infarction.

Background: To decipher the mechanisms of Angelica sinensis for the treatment of acute myocardial infarction (AMI) using network pharmacology analysis. Methods: Databases were searched for the information on constituents, targets, and diseases. Cytoscape software was used to construct the constituent-target-disease network and screen the major targets, which were annotated with the DAVID (Database for Annotation, Visualization and Integrated Discovery) tool. The cardioprotective effects of Angelica sinensis polysaccharide (ASP), a major component of A. sinensis, were validated both in H9c2 cells subjected to simulated ischemia by oxygen and glucose deprivation and in rats with AMI by ligation of the left anterior coronary artery. Results: We identified 228 major targets against AMI injury for A. sinensis, which regulated multiple pathways and hit multiple targets involved in several biological processes. ASP significantly decreased endoplasmic reticulum (ER) stress-induced cell death both in vitro and in vivo In ischemia injury rats, ASP treatment reduced infarct size and preserved heart function. ASP enhanced activating transcription factor 6 (ATF6) activity, which improved ER-protein folding capacity. ASP activated the expression of p-AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Additionally, ASP attenuated levels of proinflammatory cytokines and maintained a balance in the oxidant/antioxidant levels after AMI. Conclusion:In silico analysis revealed the associations between A. sinensis and AMI through multiple targets and several key signaling pathways. Experimental data indicate that ASP protects the heart against ischemic injury by activating ATF6 to ameliorate the detrimental ER stress. ASP's effects could be mediated via the activation of AMPK-PGC1α pathway.

Validation of simplified FABS scale to predict stroke mimics in a Chinese population undergoing intravenous thrombolysis.

OBJECTIVES: A large number of suspected stroke patients undergoing intravenous thrombolysis are stroke mimics (SMs). In this study, we sought to revise the FABS scale for screening and stratifying SMs from acute ischemic stroke (AIS) in a Chinese stroke population receiving fibrinolytic therapy. PATIENTS AND METHODS: The simplified FABS (sFABS) scale includes 4 items with 1 point for each item present: absence of facial droop, negative history of atrial fibrillation, age <50years, systolic blood pressure <150mm Hg at presentation. We evaluated consecutive suspected stroke patients undergoing intravenous thrombolysis in our stroke center for validation of sFABS scale. Diagnosis of SMs was based on absence of acute ischemic lesions on first and second diffusion weight imaging sequence in addition to an alternate diagnosis at discharge. RESULTS: A total of 190 AIS patients and 28 SMs were included in this study from December 2015 to February 2017. The sFABS scale showed excellent discrimination (C statistic: 0.928, 95% CI: 0.887-0.969, P<0.001). The Hosmer and Lemeshow goodness of fit test showed that the sFABS scale also had a good calibration (Cox and Snell R2=0.294, Nagelkerke R2=0.549). The plot of observed versus predicted risk of SMs showed high correlation (Pearson correlation coefficient: 0.983) between observed and predicted risk in our registered stroke population. CONCLUSION: The sFABS scale had excellent discrimination and good calibration abilities to predict SMs among a Chinese stroke population receiving tPA therapy. Further imaging evaluation may be necessary before the use of tPA if the sFABS score is higher.