Abstract We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high‐dose dexamethasone (HD‐DXM) plus recombinant human thrombopoietin (rhTPO), vs HD‐DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4‐day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD‐DXM plus rhTPO arm and 96 patients in the HD‐DXM monotherapy arm were included in the full analysis set. So, HD‐DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs 66.7%, P < .001) and complete response (CR, 75.0% vs 42.7%, P < .001) compared with HD‐DXM monotherapy. Response rate at 6 months was also higher in the HD‐DXM plus rhTPO arm than that in the HD‐DXM monotherapy arm (51.0% vs 36.5%, P = .02; sustained CR: 46.0% vs 32.3%, P = .043). Throughout the follow‐up period, the overall duration of response was greater in the HD‐DXM plus rhTPO arm compared to the HD‐DXM monotherapy arm ( P = .04), as estimated by the Kaplan‐Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD‐DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044.
So far, epidemiological data have revealed that the elevation of fine ambient particulate matter (aerodynamic diameter ≤2.5 μm; PM2.5) is closely associated with an exacerbation of asthma while the underlying mechanism is poorly understood. Using a murine model, we investigated the impact of PM2.5 on the development of asthma. Before OVA challenge, mice were administrated with PM2.5, phosphate-buffer saline (PBS) or control filter extracts (CFE). Results showed that compared to PBS or CSF, PM2.5 co-exposure with OVA led to a higher airway hyperresponsiveness (AHR) and a severer eosinophils infiltration. Both alveolar and interstitial macrophages are alternatively activated in OVA-challenged mice with a propensity to M2, marked by arginase-1, CD206, and YM-1. PM2.5 co-exposure dramatically elicited a YM-1 upregulation, implying an aggravated M2 polarization and macrophages recruitment. Eotaxin-1 was predominantly detected in YM-1-positive macrophages, and the level as well as those of IgE, IL-4 or IL-13 was notably increased by PM2.5 co-exposure. With IL-4/IL-13-induced transformation of bone marrow-derived macrophages (BMDM), these M2-polarized macrophages were adoptively transferred into allergic mice. An increase of CD11b+ Siglec+eosinophils was observed in these mice while in vitro, no significant polarization of BMDM was found when treated with PM2.5. Together, our findings suggested that PM2.5 could exacerbate asthma by aggravating M2-polarization, highlighting for the first time that Eotaxin-1 released from M2 macrophages plays a crucial role in asthma pathogenesis.
Human milk contains large amounts of small extracellular vesicles (sEVs) and their microRNA cargos, whereas infant formulas contain only trace amounts of sEVs and microRNAs. We assessed the transport of sEVs across the blood-brain barrier (BBB) and sEV accumulation in distinct regions of the brain in brain endothelial cells and suckling mice. We further assessed sEV-dependent gene expression profiles and effects on the dendritic complexity of hippocampal granule cells and phenotypes of EV depletion in neonate, juvenile and adult mice. The transfer of sEVs across the BBB was assessed by using fluorophore-labeled bovine sEVs in brain endothelial bEnd.3 monolayers and dual chamber systems, and in wild-type newborn pups fostered to sEV and cargo tracking (ECT) dams that express sEVs labeled with a CD63-eGFP fusion protein for subsequent analysis by serial two-photon tomography and staining with anti-eGFP antibodies. Effects of EVs on gene expression and dendritic architecture of granule cells was analyzed in hippocampi from juvenile mice fed sEV and RNA-depleted (ERD) and sEV and RNA-sufficient (ERS) diets by using RNA-sequencing analysis and Golgi-Cox staining followed by integrated neuronal tracing and morphological analysis of neuronal dendrites, respectively. Spatial learning and severity of kainic acid-induced seizures were assessed in mice fed ERD and ERS diets. bEnd.3 cells internalized sEVs by using a saturable transport mechanism and secreted miR-34a across the basal membrane. sEVs penetrated the entire brain in fostering experiments; major regions of accumulation included the hippocampus, cortex and cerebellum. Two hundred ninety-five genes were differentially expressed in hippocampi from mice fed ERD and ERS diets; high-confidence gene networks included pathways implicated in axon guidance and calcium signaling. Juvenile pups fed the ERD diet had reduced dendritic complexity of dentate granule cells in the hippocampus, scored nine-fold lower in the Barnes maze test of spatial learning and memory, and the severity of seizures was 5-fold higher following kainic acid administration in adult mice fed the ERD diet compared to mice fed the ERS diet. We conclude that sEVs cross the BBB and contribute toward optimal neuronal development, spatial learning and memory, and resistance to kainic acid-induced seizures in mice.
Shape memory polymer (SMP) foams were synthesized with three different nanoparticles (tungsten, silicon dioxide, and aluminum oxide) for embolization of cerebral aneurysms. Ultra-low density SMP foams have previously been utilized for aneurysm occlusion, resulting in a rapid, stable thrombus. However, the small cross section of foam struts can potentially lead to fracture and particulate generation, which would be a serious adverse event for an embolic device. The goal of this study was to improve the mechanical properties of the system by physically incorporating fillers into the SMP matrix. Thermal and mechanical characterization suggested minimal changes in thermal transition of the SMP nanocomposites and improved mechanical strength and toughness for systems with low filler content. Actuation profiles of the three polymer systems were tuned with filler type and content, resulting in faster SMP foam actuation for nanocomposites containing higher filler content. Additionally, thermal stability of the SMP nanocomposites improved with increasing filler concentration, and particulate count remained well below accepted standard limits for all systems. Extraction studies demonstrated little release of silicon dioxide and aluminum oxide from the bulk over 16 days. Tungstun release increased over the 16 day examination period, with a maximum measured concentration of approxiately 2.87 μg/mL. The SMP nanocomposites developed through this research have the potential for use in medical devices due to their tailorable mechanical properties, thermal resisitivity, and actuation profiles.
Key Points Although fatty acid (FA) oxidation defects have been reported in polycystic kidney disease (PKD), no studies have examined whether peroxisomes contribute to the abnormalities. We investigated peroxisome biogenesis and FA metabolism in autosomal dominant PKD models and tested whether polycystin-1 colocalized with peroxisome proteins. Our studies show that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent FA metabolism. Background Multiple studies of tissue and cell samples from patients and preclinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities, and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Methods Using control and Pkd1−/− kidney epithelial cells, we investigated peroxisome abundance, biogenesis, and morphology by immunoblotting, immunofluorescence, and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β -oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl;Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C terminus or full-length polycystin-1 colocalize with peroxisome markers by imaging studies. Results Peroxisome abundance, morphology, and peroxisome-related protein expression in Pkd1−/− cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β -oxidation was not impaired in Pkd1−/− cells, and there was no obvious accumulation of very-long-chain fatty acids in kidneys of mutant mice. Reanalysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, and provide further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full-length polycystin-1 or its C terminus, a fragment previously shown to go to the mitochondria, showed minimal colocalization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites. Conclusions Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.
Objective To study the clinical characteristics and therapeutic effect of the combination of intensive immunosuppression therapy with umbilical cord blood infusion in severe aplastic anemia (SAA) patients with infections.Methods A retrospective analysis of bacterial spectrum and treatment effect was performed for infections occurred in 27 SAA-Ⅰ patients who received antithymocyte globulin (ATG),cyclophosphamide (Cy) and cyclosporine A (CsA) followed by umbilical cord blood infusion.Results The prevalence of infections in 27 SAA-Ⅰ patients was 48.1％,among which 70 ％ were infected with bacteria (mostly gram-negative bacilli) and 30 ％ with fungal infection.Upper respiratory tract was the most common site,followed by the blood and lungs.The primary infections occurred at the median time of 9.5 d (-2-10 d)after the immunosuppressive therapy,and the initial infections of ANC were ＜ 0.2 ×109/L.Conclusion Combination of intensive immunosuppression and umbilical cord blood infusion is proven effective in treating SAA-Ⅰ.As a result,infection rate is low and can be controlled with sensitive antibiotics.
Key words:
Anemia, aplastic; Immunosuppressive therapy; Umbilical cord blood; Infection
Objective: To study the effect of aqueous extract from Melastoma dodecandrum on blood glucose in experimental hyperglycemic mice.Method: Glucose,adrenaline or streptozotocin was administrated respectively to induce three types of experimental hyperglycemic models in mice.Blood glucose was determined after ten days' administration of the aqueous extract from M.dodecandrum.Result: The aqueous extract from M.dodecandrum.could decrease blood glucose in hyperglycemic mice induced by glucose,adrenaline or streptozotocin,and it had no effect on blood glucose in normal mice.Conclusion: The aqueous extract from M.dodecandrum had effect of lowering blood glucose in hyperglycemic mice.
Background Exosomes play essential roles in cell‐to‐cell communication. Exosomes and their cargos such as proteins, lipids, and RNAs alter gene expression and metabolism in recipient cells. In previous studies we demonstrated that exosomes are not solely obtained by endogenous synthesis, but that dietary exosomes and their cargos are also bioavailable in non‐bovine species. We further demonstrated that the bioavailability of milk exosomes is less than 100%. Hypothesis Dietary intake of exosomes from bovine milk causes changes in the composition of the gut microbiota in mice. Methods C57BL/6 mice, age 3 weeks, were fed an exosome‐depleted (E‐) AIN93G‐based diet for up to 42 weeks; controls were fed an exosome‐sufficient (E+) diet. At timed intervals (age 7, 15, 45 weeks), cohorts of mice were euthanized and colon content was flash frozen in liquid nitrogen for subsequent analysis of gut microbiota by 16S rRNA gene sequencing of the V4 region using Illumina's MiSeq platform. Microbial sequences were clustered into Operational taxonomic Units (OTUs). Non‐parametric test was used for statistical analysis. Results Depending on sex and age, total 51 OTUs were differentially abundant between treatment groups; See Fig. 1 . for a heat map of the top 18 OTUs (P<0.05 for age 15 and 45 weeks). For example, the relative abundance of Firmicute classes Clostridia (Ruminococcaceae) and Verrucomicrobia classes Verrucomicrobiae (Muciniphila) were greater in mice fed E‐compared with E+ at age 15 weeks, whereas the relative abundance of Firmicute classes Clostridia (Clostridiales) was smaller in mice fed E‐ compared with E+ at age 45 weeks. Conclusions Consumption of a diet depleted of bovine milk exosomes alters certain microbial taxa in the gut microbiome in mice. Future plans Determine whether milk exosomes affect the gut bacterial ecosystem at the functional level and accounts for changes in the host transcriptome and metabolome. Support or Funding Information NIFA 2015‐67017‐23181, NIFA 2016‐67001‐25301/NIH DK107264, NIH 1P20GM104320, the Gerber Foundation, and USDA Hatch Act and W3002.
BackgroundHepatocellular carcinoma (HCC) is a highly fatal malignant cancer worldwide. Elucidating the underlying molecular mechanism of HCC progression is critical for the identification of new therapeutic targets for HCC. This study aimed to determine the role of Non-SMC condensin II complex subunit G2 (NCAPG2) in HCC proliferation and metastasis.MethodsWe detected NCAPG2 expression in tissues using immunohistochemistry, western blotting and real-time PCR. The effects of NCAPG2 on cell proliferation and metastasis were evaluated both in vitro and in vivo. Immunocytochemistry, enzyme linked immunosorbent assay, co-immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanisms.FindingsWe found that NCAPG2 is frequently upregulated in HCC tumour tissues and predicts a poor prognosis. NCAPG2 overexpression promotes HCC proliferation, migration, and invasion through activating STAT3 and NF-κB signalling pathways. Moreover, NCAPG2 is a direct target of miR-188-3p. We demonstrated the existence of a positive feedback loop between NCAPG2 and p-STAT3 and a negative feedback loop between NCAPG2 and miR-188-3p.InterpretationOur study indicates that NCAPG2 overexpression could drive HCC proliferation and metastasis through activation of the STAT3 and NF-κB/miR-188-3p pathways. These findings may contribute to the identification of novel biomarkers and therapeutic targets for HCC.FundNational Key Program for Science and Technology Research and Development (Grant No. 2016YFC0905902); the National Natural Scientific Foundation of China (Nos. 81772588, 81602058, 81773194); University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (Grant No. UNPYSCT-2016200); the Innovative Research Program for Graduate of Harbin Medical University (Grant Nos. YJSCX2017-38HYD, YJSCX2016-18HYD).
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