Vascular endothelial cells-derived exosomes synergize with curcumin to prevent osteoporosis development.

Osteoporosis has gradually become a major public health problem. Further elucidation of the pathophysiological mechanisms that induce osteoporosis and identification of more effective therapeutic targets will have important clinical significance. Experiments in vitro on bone marrow stem cells (BMSCs) subjected to osteogenic and adipogenic differentiation and in vivo on surgical bilateral ovariectomy (OVX) mouse models revealed that exosomes of vascular endothelial cells (EC-EXOs) can promote osteogenic differentiation of BMSCs and inhibit BMSC adipogenic differentiation through miR-3p-975_4191. Both miR-3p-975_4191 and curcumin can target tumor necrosis factor (TNF) and act synergistically to regulate BMSCs fate differentiation and delay the progression of osteoporosis. Our findings suggest that EC-EXOs may exert a synergistic effect with curcumin in reversing the progression of osteoporosis by targeting TNF via miR-3p-975_4191. Our study may provide therapeutic options and potential therapeutic targets for osteoporosis and thus has important clinical implications.

Exosome-derived miR-5p-72106_14 in vascular endothelial cells regulates fate determination of BMSCs.

Vascular endothelial cells have recently been shown to be associated with osteogenic activity. However, the mechanism of vascular endothelial cells promoting osteogenesis is unclear. Here, we found that exosomes secreted from human microvascular endothelial cells (HMEC-1) promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and inhibited adipogenic differentiation. Aged and ovariectomy mice treated with exosomes showed increased bone formation and decreased lipid accumulation in the bone marrow cavity. Additionally, we screened out novel exosomal miR-5p-72106_14 by miRNA-seq and confirmed that miR-5p-72106_14 promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs by inhibiting STAT1. Our results suggest that vascular endothelial cell-derived exosomes are involved in BMSC differentiation and exosomal miR-5p-72106_14 is a major factor in regulating fate determination of BMSCs.

Association between urinary 2-hydroxyethyl mercapturic acid and dyslexia among school-aged children.

Ethylene oxide is commonly used in industrial synthesis and medical disinfection. It is a known human carcinogen and has neurotoxicity. However, the association between ethylene oxide exposure and neurodevelopmental disorders remains unclear. This study aimed to evaluate the association between urinary concentrations of 2-hydroxyethyl mercapturic acid (HEMA; metabolite of ethylene oxide) and dyslexia among school-aged children. A total of 355 dyslexic children and 390 controls from three cities in China were enrolled in this case-control study from November 2017 to December 2020. Urinary HEMA was detected in 100% of the urine samples, suggesting widespread exposure to ethylene oxide in the children. Notably, the children with dyslexia had higher concentrations of urinary HEMA compared to the controls (geometric mean: 2.92 vs. 2.47 ng/mL) (P = 0.004). In the multivariable-adjusted model, urinary concentrations of HEMA were significantly associated with dyslexia risk. The individuals within the highest HEMA concentration demonstrated a 1.97-fold increased odds of dyslexia compared to those within the lowest quartile (95% confidence interval: 1.20-3.23). Thus, these findings suggested the possible link between HEMA levels and the risk of dyslexia. Further studies are warranted to validate this finding and illustrate the underlying mechanism.

Association between urinary propylene oxide metabolite and the risk of dyslexia.

Although it is a probable human carcinogen, propylene oxide is widely applied in industry and daily life. However, data on neurodevelopmental effects of propylene oxide exposure among children are extremely limited. We aimed to determine the urinary concentrations of propylene oxide metabolite among school-aged children and evaluate the potential association of propylene oxide exposure with risk of dyslexia. A total of 355 dyslexic children and 390 controls were recruited from three cities (Jining, Wuhan, and Hangzhou) in China, between 2017 and 2020. Urinary N-acetyl-S-(2-hydroxypropyl)-L-cysteine (i.e., 2-hydroxypropyl mercapturic acid; 2-HPMA) was measured as the biomarker of propylene oxide exposure. The detection frequency of 2-HPMA was 100%. After adjusting for potential confounders, the odds ratio (OR) for dyslexia per 2-fold increase in urinary 2-HPMA was 1.19 [95% confidence interval (95% CI): 1.01, 1.40, P = 0.042]. Compared with the lowest quartile of urinary 2-HPMA concentrations, children with the highest quartile of 2-HPMA had a 1.63-fold (95% CI: 1.03, 2.56, P = 0.036) significantly increased risk of dyslexia, with a dose-response relationship (P-trend = 0.047). This study provides epidemiological data on the potential association between propylene oxide exposure and the risk of dyslexia in children. Further studies are warranted to confirm the findings and reveal the underlying biological mechanisms.

Preoperative Prediction of Ki-67 Status in Breast Cancer with Multiparametric MRI Using Transfer Learning.

RATIONALE AND OBJECTIVES: Ki-67 is one of the most important biomarkers of breast cancer traditionally measured invasively via immunohistochemistry. In this study, deep learning based radiomics models were established for preoperative prediction of Ki-67 status using multiparametric magnetic resonance imaging (mp-MRI). MATERIALS AND METHODS: Total of 328 eligible patients were retrospectively reviewed [training dataset (n = 230) and a temporal validation dataset (n = 98)]. Deep learning imaging features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast enhanced T1-weighted imaging (T1+C). Transfer learning techniques constructed four feature sets based on the individual three MR sequences and their combination (i.e., mp-MRI). Multilayer perceptron classifiers were trained for final prediction of Ki-67 status. Mann-Whitney U test compared the predictive performance of individual models. RESULTS: The area under curve (AUC) of models based on T2WI,T1+C,DWI and mp-MRI were 0.727, 0.873, 0.674, and 0.888 in the training dataset, respectively, and 0.706, 0.829, 0.643, and 0.875 in the validation dataset, respectively. The predictive performance of mp-MRI classification model in the AUC value was significantly better than that of the individual sequence model (all p< 0.01). CONCLUSION: In clinical practice, a noninvasive approach to improve the performance of radiomics in preoperative prediction of Ki-67 status can be provided by extracting breast cancer specific structural and functional features from mp-MRI images obtained from conventional scanning sequences using the advanced deep learning methods. This could further personalize medicine and computer aided diagnosis.

Increased Circulating of CD54highCD181low Neutrophils in Myelodysplastic Syndrome.

Myelodysplastic syndromes (MDSs) are a group of heterogeneous hematopoietic stem/progenitor cells clonal diseases, characteristic features with myeloid dysplasia, leading to abnormality of neutrophils. Recent studied have showed that neutrophils act not only as professional killers, but also as regulators of innate and adaptive immune in infection and inflammatory condition. The CD54highCD181low neutrophils are a kind of reverse-transmigrated neutrophils characterized proinflammatory phenotype. We investigated the frequency and functional properties of circulating CD54highCD181low neutrophils in patients with untreated MDS. Frequency of CD54highCD181low neutrophils was significantly increased in MDS patients and related to the severity of the disease. Furthermore, CD54highCD181low neutrophils suppressed CD8+ T cells functions in vitro. CD54highCD181low neutrophils lead to upregulation of PD1 on CD8+ T cells. Higher CD54highCD181low neutrophils were related to poor prognosis and more infections. The frequency of CD54highCD181low neutrophils decreased in high risk MDS patients who had response after treatment with decitabine. Overall, we identified CD54highCD181low neutrophils expanded in MDS. The exact mechanisms of increased CD54highCD181low neutrophils and its effect on immune function remain to be elucidated.

Abnormal populations and functions of natural killer cells in patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis that lead to leukemia. Disorders of the immune system serve important functions in the pathophysiology and progression of this disease. Different levels or mechanisms of natural killer (NK) cells in patients with MDS have been measured in previous studies, making it challenging to understand the pathogenesis of NK cytotoxicity. The present study investigated the frequency of NK cell-mediated antibody-dependent cellular cytotoxicity and explored the function of NK cells by their activating receptors, inhibition signals, degranulation and cytotoxicity factors. In the present study, levels of cluster of differentiation (CD)3-CD56+ NK cells, CD16+-expressing NK cells and subset CD56dim NK cells were decreased in the peripheral blood of patients with MDS. Altered expression of NK protein 44, NK group 2 member D, killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) and KIR2DL3 on NK cell effector signaling pathways may trigger tumor cell lysis in patients with MDS. The weak cellular adhesion and decreased cytotoxicity of NK cells may lead to ineffective antitumor activity in MDS. These observations suggested that NK cells may serve as immunological determinants in MDS and may permit the development of NK cell-based immunotherapy for the treatment of patients with MDS.

Effects of Transport Temperature on the Stability of Inflammatory, Hemostasis, Endothelial Function, and Oxidative Stress Plasma Biomarker Concentrations.

BACKGROUND: A number of studies in critically ill patients are conducted outside the hospital. Specimens should ideally be transported from out-of-hospital setting to a laboratory using dry ice, but this approach is expensive and may not be feasible in some circumstances. We, therefore, examined the impact of temperature during transport of specimens on the precision of biomarker concentrations. OBJECTIVE: To determine the effects of transport temperature conditions on biomarker concentrations in specimens processed within 1 h of collection. METHODS/PATIENTS: We simulated transport by storing specimens at four temperature conditions: packaged at -80°C (control), on dry ice (-79°C), on cold gel packs (4°C), and at room temperature (RT, 21°C). We examined eight biomarkers spanning four signaling domains- inflammation, hemostasis, endothelial dysfunction, and oxidative stress. We calculated mean, median, and percent difference for each biomarker concentration compared with the control transport temperature at -80°C in 26 subjects (16 hospitalized with severe sepsis and 10 non-hospitalized volunteers). RESULTS: Patients with severe sepsis had log-fold higher median concentrations of IL-6, hs-CRP, D-dimer, E-selectin, sICAM-1, and sVCAM-1 compared with non-hospitalized volunteers (P <0.05). When specimens were combined, we observed a ≤7% difference in the mean and median IL-6, hs-CRP, D-dimer, PAI-1, E-selectin, s-ICAM, s-VCAM, and nitrite concentrations for dry ice and cold gel packs transport compared with transport at -80°C (P>0.05). Larger differences (up to 12%) were observed when biomarker concentrations for PAI-1 and s-VCAM at room temperature were compared with transport at -80°C (P >0.05). CONCLUSIONS: Select inflammatory, coagulation, endothelial dysfunction, and oxidative stress biomarkers can be transported at 4°C on gel packs for 24 h with minimal effects on precision.

[Expression and Significance of HOXA9 in Patients with Myelodysplastic Syndromes].

OBJECTIVE: To investigate the expression pattern of HOXA9 in myelodysplastic syndrome (MDS) patients and its relation with clinical characteristics and treatment response. METHODS: The mRNA and protein expression levels of HOXA9 in bone marrow cells from 33 cases of MDS, 12 cases of AML, 20 cases of ITP and 18 normal controls were detected by real-time guautitative PCR(RT-PCR) and flow cytometry, respectively. RESULTS: The percentage of HOXA9(+)/CD34(+) and HOXA9(+)/CD34(+)CD38(-) in MDS patients were significantly higher than that in control group (P<0.05), and the mRNA and protein expression of HOXA9 in MDS patients had a similar trend. The percentages of HOXA9(+)/CD34(+) and HOXA9(+)/CD34(+)CD38(-) before decitabine treatment were (50.64±27.59)% and (55.67±28.57)% respectively, which were both higher than those in control group (P<0.05). After decitabine treatment, expression of HOXA9 significantly decreased (P<0.05). CONCLUSION: HOXA9 is overexpressed in MDS patients and associated with several clinical characteristics. The detection of HOXA9 expression may have guide roles for diagnosis and treatment of MDS patients.

Comparison of praziquantel pharmacokinetics and tissue distribution in fresh and brackish water cultured grass carp (ctenopharyngodon idellus) after oral administration of single bolus.

BACKGROUND: Praziquantel (PZQ) is an effective pesticide against monogeneans. Its pharmacokinetics in fish may be affected by water environment and temperature. The present study was designed to compare the pharmacokinetics, tissue distribution, and elimination of PZQ in freshwater-acclimated grass carp and brackish water cultured grass carp. Plasma and tissue PZQ concentrations were determined after a single 10 mg/kg oral PZQ dose. RESULTS: The datas of plasma and tissues drug concentration was calculated by the software SPSS 13.0. According to the One-Way ANOVA, the results showed that the salinity had a significant effect on the drug concentration of plasma (p < 0.01), muscle (p < 0.01), liver (p < 0.01) and kidney (p < 0.01) in the all sampling time points between the brackish water grass carps and the freshwater grass carps, wherein, PZQ plasma and tissue concentrations in the brackish water group were constantly lower than that in the freshwater group. The peak PZQ levels of plasma, muscle, liver, and kidneys in the brackish water group were 0.76 µg/ml, 0.51 µg/g, 2.7 µg/g, and 2.99 µg/g, respectively; and that in the freshwater group were 0.91 µg/ml, 0.62 µg/g, 3.87 µg/g, and 3.39 µg/g, respectively. The elimination half-lives (t1/2ß) in plasma and all tissues of the freshwater group were significantly longer than that in the brackish water group. The elimination half-lives (t1/2ß) of plasma, muscle, liver and kidneys in brackish water grass carps were 56.46, 36.17, 15.31, and 132.64 h, respectively; and that in the freshwater grass carps were 71.15, 44.88, 23.86, and 150.23 h, respectively. CONCLUSION: These findings indicate that water environment affects the tissue distribution and elimination of PZQ in grass carps, the elimination in brackish water grass carps is more rapid than that in fresh water grass carps and tissue concentrations of brackish water grass carps are lower than that in freshwater grass carps after orally administrating the same dosage at the same water temperature. We speculate that the main excretion pathway of the drug is through renal elimination, and the decreased kidney function in brackish water grass carps is likely responsible for the considerable difference in pharmacokinetics between the two groups of grass carps.

[Recent advances of studies on abnormal HOX gene in myelodysplastic syndromes and its molecular mechanisms].

HOX gene encodes a group of homeodomain transcription factors which are highly conserved. The caudal-type homeobox (CDX) , ten-eleven translocation (TET) genes and polycomb group (PcG) , trithorax group (TrxG) proteins act as upstream regulators of HOX genes that manipulate the targeted gene expression through genetic and epigenetic mechanisms. The abnormal expression of HOX genes and their fusions contribute to myelodysplastic syndromes (MDS) pathogenesis. Aberrant DNA methylation and NUP98-HOX translocation serve as molecular mediators of dysfunction in MDS which can be used for the evaluation of biology and therapy. This article provides an overview of recent advances of studies on HOX gene and its abnormal molecular mechanisms, as well as potential correlation with MDS.