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Dysplasia and intramucosal esophageal squamous cell carcinoma (ESCC) frequently go unnoticed with white-light endoscopy and, therefore, progress to invasive tumors. If suitable targets are available, fluorescence molecular endoscopy might be promising to improve early detection. Microarray expression data of patient-derived normal esophagus (n = 120) and ESCC samples (n = 118) were analyzed by functional genomic mRNA (FGmRNA) profiling to predict target upregulation on protein levels. The predicted top 60 upregulated genes were prioritized based on literature and immunohistochemistry (IHC) validation to select the most promising targets for fluorescent imaging. By IHC, GLUT1 showed significantly higher expression in ESCC tissue (30 patients) compared to the normal esophagus adjacent to the tumor (27 patients) (p &lt, 0.001). Ex vivo imaging of GLUT1 with the 2-DG 800CW tracer showed that the mean fluorescence intensity in ESCC (n = 17) and high-grade dysplasia (HGD, n = 13) is higher (p &lt, 0.05) compared to that in low-grade dysplasia (LGD) (n = 7) and to the normal esophagus adjacent to the tumor (n = 5). The sensitivity and specificity of 2-DG 800CW to detect HGD and ESCC is 80% and 83%, respectively (ROC = 0.85). We identified and validated GLUT1 as a promising molecular imaging target and demonstrated that fluorescent imaging after topical application of 2-DG 800CW can differentiate HGD and ESCC from LGD and normal esophagus.

Ovarian cancer is one of the most lethal gynecologic malignancies for women. Due to the lack of efficient target therapy, the overall survival rate for patients with advanced ovarian cancer is still low. Illustrating the molecular mechanisms dictating ovarian cancer progression is critically important to develop novel therapeutic agents. Here, we found that RNA-binding motif protein 11 (RBM11) was highly elevated in ovarian cancer tissues compared with normal ovary, while RBM11 depletion in ovarian cancer cells resulted in impaired cell growth and invasion. Moreover, knockdown of RBM11 also retarded tumor growth in the A2780 ovarian cancer xenograft model. Mechanically, we found that RBM11 positively regulated Akt/mTOR signaling pathway activation in ovarian cancer cells. Thus, these results identify RBM11 is a novel oncogenic protein and prognostic biomarker for ovarian cancers.

Farfarae Flos is a traditional Chinese medicine that has long been used to treat allergies. In this study, we aimed to investigate the effect of a petroleum extract of Farfarae Flos (PEFF) in a mouse model of allergic rhinitis (AR) and to explore the underlying molecular mechanisms of action. An animal model of AR was established by sensitization and challenge of BALB/c mice with ovalbumin (OVA). PEFF was administered intranasally and AR nasal symptoms were assessed on a semi-quantitative scale according to the frequencies of nose rubbing and sneezing and the degree of rhinorrhea. The mechanism of action of PEFF was evaluated by histological analysis of nasal mucosa architecture and inflammatory status; ELISA-based quantification of serum OVA-specific IgE, interferon-γ (IFN-γ), and interleukin-4 (IL-4) concentrations; and immunohistochemical and western blot analysis of T-bet and GATA3 protein expression in nasal mucosa and spleen tissues. The results showed intranasal administration of PEFF alleviated AR symptom scores and reduced both the infiltration of inflammatory cells and tissue damage in the nasal mucosa. PEFF significantly decreased serum concentrations of OVA-specific IgE (P

Carbonic anhydrase (CA) inhibitors have a long history of safe clinical use as mild diuretics, in the treatment of glaucoma and for altitude sickness prevention. In this study, we aimed to determine if CA inhibition may be an alternative approach to control thrombosis. We utilized a high-resolution dynamic imaging approach to provide mechanistic evidence that CA inhibitors may be potent anti-procoagulant agents in vitro and effective anti-thrombotics in vivo. Acetazolamide and methazolamide, while sparing platelet secretion, attenuated intracellular chloride ion entry and suppressed the procoagulant response of activated platelets in vitro and thrombosis in vivo. The chemically similar N-methyl acetazolamide, which lacks CA inhibitory activity, did not affect platelet procoagulant response in vitro. Outputs from rotational thromboelastometry did not reflect changes in procoagulant activity and reveal the need for a suitable clinical test for procoagulant activity. Drugs specifically targeting procoagulant remodeling of activated platelets, by blockade of carbonic anhydrases, may provide a new way to control platelet-driven thrombosis without blocking essential platelet secretion responses.

Platelets are small anucleate blood cells1,2 with critical roles in haemostasis, thrombosis, inflammation, vascularization, innate immunity and tissue regeneration3,4. In vitro-derived platelets, as an alternative to native platelets, are attractive for fundamental research because of their rapid genetic tractability, as vectors for drug and genetic component delivery5 and in clinical platelet transfusion. At present, however, their very low production rate, and poor agonist responsiveness, are major obstacles. Platelets are formed by fragmentation from mature polyploid megakaryocytes (MKs), their precursor cells6, although the process of their generation remains incompletely understood7,8. Bone marrow is proposed to be the main site of platelet production, however indirect evidence since the 1930s9,10 and recent direct observation11 has shown that the lung can also be a primary site of platelet biogenesis. Here we established an ex vivo mouse heart-lung model (Fig. 1a) through which we were able to perfuse murine MKs. Remarkably, we could show for the first time that MKs, despite their large size, can pass multiple times through the lung vasculature, and that this leads to the generation of very large numbers of fully functional platelets (up to 3,000 per megakaryocyte7,12). Using this system and a novel in vitro microfluidic chamber we show roles for ventilation, oxygenation and healthy pulmonary endothelial cells in platelet generation. We show that MKs undergo enucleation upon repeated passage through pulmonary vasculature before fragmentation to generate platelets, with this final process dependent on the actin regulator TPM4. This advances our understanding of platelet formation in the body and establishes a novel approach to generate large numbers of them outside the body.

OBJECTIVE To evaluate the ability of quantitative MRI parameters for predicting dysthyroid optic neuropathy (DON). METHODS We retrospectively collected and analyzed the clinical features and 3.0 T MRI data of 59 patients with Graves orbitopathy (GO), with (n = 26) and without DON (n = 33). We compared MRI quantitative parameters, including the modified muscle index (mMI), proptosis, volume of intra-orbital fat, mean apparent diffusion coefficient value, and T2 value of the optic nerve among patients with and without DON. A logistic regression analysis was performed to identify the risk factors associated with DON. Moreover, we performed a receiver operating characteristic curve analysis and decision curve analysis to evaluate the diagnostic performance of the identified parameters for DON. RESULTS We studied 118 orbits (43 and 75 with and without DON, respectively). The mMI and mean T2 value of the optic nerve were significantly greater in orbits with DON (p

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a promising target for treating dyslipidemia and atherosclerosis. Circulating PCSK9 levels are closely related to hepatic steatosis severity and endogenous estrogen levels. Resveratrol (RSV) is a phytoestrogens that protects against atherosclerosis and hepatic steatosis. Thus, we sought to determine whether RSV had the activities to inhibit PCSK9 expression and to attenuate lipid accumulation in free fatty acid (FFA)-induced L02 cells via ERα pathway. In this study, RSV (10, 20 μM) were cultured with L02 cells in the presence of FFA (oleate:palmitate = 2:1). RSV significantly reduced the number of lipid droplets and intracellular TG in steatotic L02 cells, and Oil red O staining and Nile red staining had the same results. Western blot analysis showed that RSV significantly reduced apoB secretion and intracellular microsomal triglyceride transporter (MTP) expression under lipid-rich conditions. Treatment with RSV reduced expression of PCSK9 while maintaining LDL receptor (LDLR) expression and LDL uptake. RSV decreased SREBP-1c expression at both mRNA and protein levels. In addition, RSV significantly reduced the expression of liver X receptor α (LXRα) mRNA in L02 cells, but did not affect the expression of liver X receptor β (LXRβ) mRNA. The luciferase reporter assays suggested that RSV inhibited SREBP-mediated transcription of PCSK9. Finally, these results could be partly reversed by Estrogen receptor α (ERα) gene silencing. These results suggest that RSV attenuates steatosis and PCSK9 expression through down-regulation of SREBP-1c expression, at least in part through ERα-mediated pathway.

Background Although the genetic spectrum of human colorectal cancer (CRC) is mainly characterized by APC, KRAS and TP53 mutations, driver genes in tumor initiation have not been conclusively demonstrated. In this study, we aimed to identify novel markers for CRC. Methods We performed exome analysis of sporadic colorectal cancer (sCRC) coding regions to screen loss of function (LoF) mutation genes, and carried out systems-level approaches to confirm top rank gene in this study. Results We identified loss of BMP5 is an early event in CRC. Deep sequencing identified BMP5 was mutated in 7.7% (8/104) of sCRC samples, with 37.5% truncating mutation frequency. Notably, BMP5 negative expression and its prognostic value is uniquely significant in sCRC but not in other tumor types. Furthermore, BMP5 expression was positively correlated with E-cadherin in CRC patients and its dysregulation play a vital role in epithelial-mesenchymal transition (EMT), thus triggering tumor initiation and development. RNA sequencing identified, independent of BMP/Smads pathway, BMP5 signaled though Jak-Stat pathways to inhibit the activation of oncogene EPSTI1. Conclusions Our result support a novel concept that the importance of BMP5 in sCRC. The tumor suppressor role of BMP5 highlights its crucial role in CRC initiation and development. Electronic supplementary material The online version of this article (10.1186/s12943-018-0925-7) contains supplementary material, which is available to authorized users.

To explore radiological changes of the lacrimal gland (LG) in Graves' ophthalmopathy (GO) based on multi-parametric quantitative MRI and its clinical utility in LG diagnosis and activity in GO.We enrolled 99 consecutive patients with GO (198 eyes) and 12 Graves' Disease (GD) patients (24 eyes) from July 2018 to June 2020. Clinical, laboratory, and MRI data were collected at the first visit. Based on clinical activity scores, eyes with GO were subdivided into active and inactive groups. T2-relaxation time (T2) and the absolute reduction in T1-relaxation time (ΔT1) were determined. After MRI and processing, we performed descriptive data analysis and group comparisons. Novel logistic regression predictive models were developed for diagnosing and staging GO. Diagnostic performance of MRI parameters and models was assessed by receiver operating characteristic curve analysis.LG in GO group had significantly higher T2 and ΔT1 values than the GD group [106.25(95.30,120.21) vs. 83.35(78.15,91.45), P0.001, and 662.62(539.33,810.95) vs. 547.35(458.62,585.57), P = 0.002, respectively]. The GO group had higher T2 of LG indicating higher disease activity [110.93(102.54,127.67) vs. 93.29(87.06,101.96), P 0.001]. Combining T2 and ΔT1 values of LG, Model I had higher diagnostic value for distinguishing GO from GD (AUC=0.94, 95 %CI: 0.89,0.99, P0.001). Meanwhile, T2 of LG had higher diagnostic value for grading GO activity (AUC = 0.84, 95 %CI: 0.76,0.92, P0.001).Multi-parametric quantitative MRI parameters of the LG in GO were significantly altered. Novel models combining LG T2 and ΔT1 values showed excellent predictive performances in diagnosing GO. Furthermore, T2 of LG showed practical utility for staging GO.

Background: Calorie restriction (CR) has been widely recognized for its effect in reducing body weight and alleviating diabetes in humans, as well as prolonging life span in animal studies. Gut microbiome shifts contribute to part of the effects of CR, but little is known regarding their influences except on metabolism and immunity.Methods: We combined the human population-based (metagenomic, metatranscriptomics shotgun sequencing data) and mice-based approaches to revealed microbial determinants that could contribute to successful weight loss.Results: Microbiome changes are linked to changes in blood metabolome and hormones, which eventually correlate to brain functional changes as studied using functional magnetic resonance imaging (fMRI). Brain functional shifts indicate response of central neural system (CNS) to CR, and microbiome constitutes thekeystone of gut-brain axis. Animal experiment further reaffirms the gut microbiome changes, metabolic and hormonal shifts of CR, while proteomic analysis of brain tissues suggest that epigenetic modifications of key proteins could explain responses of CNS to CR.Conclusion: Our study establishes linkage between CR, gut microbiome, metabolome/ hormones and CNS function, and demonstrates that CR has multi-facet, coordinated effects on the host, of which many could contribute to weight loss and other beneficial effects.

SHARPIN (Src homology 3 and multiple ankyrin repeat domains protein (SHANK)- associated RH domain-interacting protein) as part of the linear ubiquitin chain assembly complex (LUBAC) catalyses the addition of linear (Met1-linked) ubiquitin chains to substrates. As part of this complex SHARPIN acts as a multi-functional modulator of immune/inflammatory responses through regulation of NfkB activation. In addition, SHARPIN can act as a negative regulator of integrin function. Despite platelets being anucleate cells several studies have determined potential roles for both ubiquitination and NfkB in regulating platelet function. However, little is known about either linear ubiquitination and/or SHARPIN in mouse platelets. In this study, we evaluated platelet function in mice with impaired SHARPIN expression. We confirmed that SHARPIN was expressed in platelets from wild-type mice but not in mice homozygous for SHARPINcpdmallele (cpdm/cpdm) and that this correlated with a reduction in linear ubiquitination. Platelet function in response to thrombin was unaffected. In contrast, CRP-XL-and U46619-mediated platelet responses and thrombus formation under flow on a collagen-coated surface were significantly reduced in the cpdm/cpdm mice. This was associated with impaired U46619-mediated intracellular signalling as well as a reduction in CRP-mediated ERK phosphorylation. Despite the reported role for NfκB in regulating platelet function, inhibiting IκBα phosphorylation did not recapitulate the cpdm/cpdm phenotype. Together, these data indicate that the lack of SHARPIN and linear ubiquitination results in impaired thrombosis and platelet functional responses to CRP and U46619. This phenotype is independent of NfκB pathway inhibition but may involve alternative signalling pathways regulated by linear ubiquitination.Key PointsSHARPIN plays an essential role in platelet linear protein ubiquitination and CRP and U46619-mediated platelet functionIn vitro thrombosis is significantly impaired in SHARPIN deficient mice

The reactivity of platelets, which play a key role in the pathogenesis of atherothrombosis, is tightly regulated. The integral membrane protein tetherin/bone marrow stromal antigen-2 (BST-2) regulates membrane organization, altering both lipid and protein distribution within the plasma membrane. Because membrane microdomains have an established role in platelet receptor biology, we sought to characterize the physiological relevance of tetherin/BST-2 in those cells. To characterize the potential importance of tetherin/BST-2 to platelet function, we used tetherin/BST-2−/− murine platelets. In the mice, we found enhanced function and signaling downstream of a subset of membrane microdomain–expressing receptors, including the P2Y12, TP thromboxane, thrombin, and GPVI receptors. Preliminary studies in humans have revealed that treatment with interferon-α (IFN-α), which upregulates platelet tetherin/BST-2 expression, also reduces adenosine diphosphate–stimulated platelet receptor function and reactivity. A more comprehensive understanding of how tetherin/BST-2 negatively regulates receptor function was provided in cell line experiments, where we focused on the therapeutically relevant P2Y12 receptor (P2Y12R). Tetherin/BST-2 expression reduced both P2Y12R activation and trafficking, which was accompanied by reduced receptor lateral mobility specifically within membrane microdomains. In fluorescence lifetime imaging-Förster resonance energy transfer (FLIM-FRET)–based experiments, agonist stimulation reduced basal association between P2Y12R and tetherin/BST-2. Notably, the glycosylphosphatidylinositol (GPI) anchor of tetherin/BST-2 was required for both receptor interaction and observed functional effects. In summary, we established, for the first time, a fundamental role of the ubiquitously expressed protein tetherin/BST-2 in negatively regulating membrane microdomain–expressed platelet receptor function.

Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, while there is still no medicine available. Farnesoid X receptor (FXR) is considered as a potential target for the treatment of NAFLD, and there are several FXR agonists reached in clinical trials. Based on better safety, industry and academia are pursuing development of the partial FXR agonists. To extend the chemical space of existing partial FXR agonists, we performed a structure-activity relationship study based on previously reported partial agonist 1 by using bioisosteric strategy. All of these efforts resulted in the identification of novel partial FXR agonist 13, which revealed the best agonistic activity in this series. Notably, compound 13 significantly alleviated the hepatic steatosis and hepatic function index in methionine-choline deficient (MCD) induced db/db mice, a classical nonalcoholic steatohepatitis (NASH) model widely used in preclinical evaluation. These results suggested that partial FXR agonist 13 might be a promising lead compound worthy further researches.

The main purpose of this study was to perform a meta-analysis to assess the interaction between smoking and nine genes (GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, SULT1A1, hOGG1, XRCC1 and p53) on colorectal cancer, gastric cancer, liver cancer and oesophageal cancer. Published articles from the PubMed, ISI and EMBASE databases were retrieved. A total of 67 case-control studies or nested case-control studies were identified for the analysis. The pooled jodds ratio (OR) with 95% confidence interval (CI) was calculated using the random effect model. The overall study showed that the GSTM1 polymorphism was associated with the risk of the four digestive cancers among Asian population (OR 1.284, 95% CI: 1.122-1.470, p: 0). Subgroup analyses by cancer site showed that GSTM1 null genotype increased the gastric cancer risk in total population (OR 1.335, 95% CI: 1.145-1.556, p: 0). However, the association of GSTM1 null genotype with the oesophageal cancer risk was found in smokers (OR 1.382, 95% CI: 1.009-1.894, p:0.044), but not in non-smokers (OR 1.250, 95% CI: 0.826-1.891, p:0.290). Moreover, smokers with the CYP1A1 IIe462Val polymorphism were at an increased cancer risk in Asian population (OR=1.585, 95% CI 1.029-2.442, p: 0.037). None of the other gene-smoking interactions was observed in the above cancers. This meta-analysis reveals two potential gene-smoking interactions, one is between smoking and GSTM1 on oesophageal cancer, and the other is between smoking and CYP1A1 IIe462Val on the four cancers in Asian population. Future studies need to be conducted to verify the conclusions.

An efficient decoloration method for polysaccharides from the sprouts of Toona sinensis (A. Juss.) Roem (PSTS) by anion exchange macroporous resins (AEMR) was investigated in the present paper. The results suggested that D941 resin offered better decoloration efficiency than other tested resins. Based on single-factor experiments, the optimal decoloration parameters of D941 resin were obtained as follows: temperature of 45°C, sample initial concentration of 30mg/ml, pH value of 8.5, static decoloration time of 90min, dynamic decoloration processing volume of 5.5BV with the flow rate of 2BV/h. Decoloration ratio, PSTS recovery ratio and selectivity coefficient were 91.94±1.23%, 90.05±2.35% and 10.92±0.63, respectively. Most of pigment impurities were successfully removed from PSTS solutions after treated by D941 resin, and there was no significant difference in carbohydrate concentration, characteristic groups and molecular weight. Compared with H2O2 oxidation and activated carbon adsorption, this developed method is superior.

Growing evidence has indicated that prognostic biomarkers have a pivotal role in tumor and immunity biological processes. TP53 mutation can cause a range of changes in immune response, progression, and prognosis of colorectal cancer (CRC). Thus, we aim to build an immunoscore prognostic model that may enhance the prognosis of CRC from an immunological perspective. We estimated the proportion of immune cells in the GSE39582 public dataset using the CIBERSORT (Cell type identification by estimating relative subset of known RNA transcripts) algorithm. Prognostic genes that were used to establish the immunoscore model were generated by the LASSO (Least absolute shrinkage and selection operator) Cox regression model. We established and validated the immunoscore model in GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) cohorts, respectively, significant differences of overall survival analysis were found between the low and high immunoscore groups or TP53 subgroups. In the multivariable Cox analysis, we observed that the immunoscore was an independent prognostic factor both in the GEO cohort (HR (Hazard ratio) 1.76, 95% CI (confidence intervals): 1.26&ndash, 2.46) and the TCGA cohort (HR 1.95, 95% CI: 1.20&ndash, 3.18). Furthermore, we established a nomogram for clinical application, and the results suggest that the nomogram is a better predictive model for prognosis than immunoscore or TNM staging.

Mutations in the DNA damage repair (DDR) pathway are frequently detected in colorectal cancer (CRC). The dysregulation of miRNAs, such as oncogenes or tumor suppressors, participates in CRC tumorigenesis. A previous study showed that low miR-3607 expression correlated with poor survival in prostate cancer patients, but its role in CRC remains unclear. In this study, we analyzed miR-3607 expression Pan-Cancer data from the NCI’s Genomic Data Commons (GDC) and found that miR-3607 was downregulated in lymphatic invasion patients and in recurrent cancer and correlated with Pan-Cancer patient survival. Functional studies indicated that the overexpression of miR-3607 decreased CRC cell proliferation, migration and invasion. Additionally, we used gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and a protein–protein interaction network to demonstrate that miR-3607 affects the DDR pathway. Luciferase reporter and apoptosis assays confirmed that DNA damage inducible 1 homolog 2 (DDI2) is the functional target of miR-3607. Therefore, miR-3607 inhibits the tumorigenesis of CRC probably by suppressing the oncogene DDI2, and it might serve as a novel target for CRC prediction and therapy.

MicroRNAs (miRs) have been reported to be key regulators in numerous types of cancer. The aim of the present study was to investigate the role of miR-494 in ovarian cancer. Expression of miR-494 was analyzed in ovarian cancer tissues and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-494 mimic or negative control was transiently transfected into A2780 and SKOV3 cell lines. A cell counting kit-8 assay was performed to assess the effects of miR-494 on cell proliferation, and flow cytometry was used to evaluate the apoptotic rate. The target gene of miR-494 was detected by luciferase assay. Expression of fibroblast growth factor receptor 2 (FGFR2) was identified using RT-qPCR and western blotting. In the present study, decreased expression of miR-494 was observed in ovarian cancer samples and cell lines. Overexpression of miR-494 inhibited ovarian cancer cell proliferation by inducing apoptosis. Additional investigation indicated that FGFR2 was a direct target of miR-494. Taken together, the results of the present study suggested that miR-494 suppressed ovarian cancer cell proliferation by inducing apoptosis via targeting FGFR2.

Metastasis is a well-known poor prognostic factor and primary cause of mortality in patients with colorectal cancer (CRC). Recently, with the progress of high through-put sequencing, aberrantly expressed non-coding RNAs (ncRNAs) were found to participate in the initiation and development of cancer. However, the mechanisms of ncRNA-mediated regulation of metastasis in CRC remain largely unknown. In this study, we systematically analyzed the expression network of microRNAs (miRNAs) and genes in CRC metastasis using bioinformatics, and discovered that the miR-581/SMAD7 axis could be a potential factor that drives CRC metastasis. A dual luciferase report assay and protein analysis confirmed the binding relationship between miR-581 and SMAD7. Further functional assays revealed that miR-581 inhibition could suppress cell proliferation and induce apoptosis in SW480 cells. Up-regulation or down-regulation of miR-581 could both affect cell invasion capacity and modulate epithelial to mesenchymal transition (EMT) via a SMAD7/TGF&beta, signaling pathway. In conclusion, our findings elucidated that miR-581/SMAD7 could be essential for CRC metastasis, and may serve as a potential therapeutic target for CRC patients.

Mutations in transforming growth factor beta receptor II (TGFBR2) are detected in up to 30% of overall colorectal cancer (CRC). Dysregulation of some microRNAs participated in the CRC pathogenesis. In this study, we used the gene ontology analyses, the Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene set enrichment analysis to indicate that miR-3191 was involved in the regulation of transforming growth factor beta (TGF-BETA) signal pathway in CRC. These bioinformatics results were supported by data obtained from CRC samples and experiments in vitro. The luciferase reporter assay was used to confirm that miR-3191 modulates TGF-BETA signal pathway by targeting TGFBR2. By transwell migration and invasion assays, we showed that miR-3191 promoted CRC cell migration and invasion by downregulating TGFBR2. And it may serve as a novel therapeutic strategy for treating CRC patients.

We analyzed surveillance data for 2 sentinel hospitals to estimate the influenza-associated severe acute respiratory infection hospitalization rate in Beijing, China. The rate was 39 and 37 per 100,000 persons during the 2014–15 and 2015–16 influenza seasons, respectively. Rates were highest for children

Multi-User Detection (MUD) for uplink grant-free Non-orthogonal Multiple Access (NOMA) has received much attention recently. In this paper, we consider the scenario in which a Base Station (BS) is equipped with multiple antennas, and propose a Compressive Sensing-based Hard Fusion Algorithm (CS-HFA) to realize MUD. More explicitly, we detect the user activity information by a conventional CS algorithm at each antenna, and then amalgamate the detected user activity information to derive an active user set. Finally, we can use the obtained active user set to estimate the active users' data. The proposed CS- HFA with low complexity for uplink grant-free Single-Input Multiple-Output Non-Orthogonal Multiple Access (SIMO-NOMA) systems can achieve better BER performance than traditional CS-based MUD in the NOMA system with single antenna at the BS.

Sporadic colorectal cancer (sCRC) is one of the leading causes of cancer death worldwide. As a highly heterogeneous complex disease, the currently reported classical genetic markers for sCRC, including APC, KRAS, BRAF, and TP53 gene mutations and epigenetic alterations, can explain only some sCRC patients. Here, we first reported a deleterious c.551C>T mutation in SARDH in sCRC. SARDH was identified as a novel tumor suppressor gene and was abnormally decreased in sCRC at both the transcriptional and the translational level. SARDH mRNA levels were also down-regulated in oesophageal cancer, lung cancer, liver cancer, and pancreatic cancer in the TCGA database. SARDH overexpression inhibited the proliferation, migration, and invasion of CRC cell lines, whereas its depletion improved these processes. SARDH overexpression was down-regulated in multiple pathways, especially in the chemokine pathway. The SARDH transcript level was positively correlated with the methylation states of CXCL1 and CCL20. Therefore, we concluded that SARDH depletion is involved in the development of sCRC.

MiRNA regulation is a crucial way of epigenetic changes. Mir-32 has been reported in several studies as an oncogene, however, its role and target in colorectal cancer (CRC) remains unclear. In this study, we aimed to explore the role of miR-32 in CRC using bioinformatic analysis and functional assays. We collected 28 pairs of CRC tumor tissues and adjacent normal tissues and confirmed miR-32 was significantly upregulated in CRC. Expression and clinical data from The Cancer Genome Atlas (TCGA) identified miR-32 expression is associated with CRC lymphatic invasion, metastasis, and correlates with patients' poor survival. Functional studies demonstrated that overexpression of miR-32 in LoVo cells promoted cell proliferation and migration, whereas inhibition of miR-32 in HCT 116 cells showed the opposite results. Using bioinformatics, we identified Bone morphogenetic protein 5 (BMP5) is a direct target of miR-32, and loss of tumor suppressor BMP5 may partially due to the miR-32 dysregulation. The inverse correlation between miR-32 and BMP5 was observed in CRC, especially in advanced tumor patients. Moreover, cotransfection of miR-32 mimics and BMP5 recombinant vector in LoVo cells demonstrated that BMP5 could reverse the oncomir effect of miR-32. Taken together, our results suggested a significant role of miR-32/BMP5 axis in CRC tumorigenesis.

Variations in amino acid and volatile component contents, and in total flavonoid, polyphenol contents and their vitro antioxidant activities at different aging times of pomelo wine were investigated; scavenging rates against DPPH, ABTS, and ferric reducing antioxidant powers were also explored. Most amino acids reached maximum values in the third aging year; and volatile components of pomelo wine also indicated good wine quality in the third year. Total flavonoid and polyphenol contents in pomelo wine were increased and antioxidant activities enhanced during the first 3 years. Samples aged for 3 years had the highest total flavonoid and total polyphenol contents, and the strongest antioxidant activities (38.23±2.16% for DPPH· scavenging effect, 91.84±4.14% for ABTS· scavenging effect, and 0.90±0.07 mmol/L for FRAP value). These parameters gradually decreased after the 3 year period. A significant (p

Given that mismatch repair (MMR) system plays an important role in recognizing and removing insertion/deletion mutations which occur during DNA replication, common variants associated with impaired MMR system may thus increase risk of colorectal cancer (CRC). Therefore, we aimed to demonstrate the associations between common variants in two MMR genes (hMLH1 and hMSH2) and CRC risk.We genotyped 10 intronic/promoter single-nucleotide polymorphisms (SNPs) of hMLH1 and hMSH2 in 451 CRC patients and 630 controls. Associations between genotypes and CRC risk were estimated using odds ratios and 95 % confidence intervals. Gene-gene interactions, as well as gene-environment interactions on CRC risk were also investigated.We found that IVS15-214TC and IVS11 + 107AG of hMSH2 were significantly associated with CRC risk. In dominant model, variant carriers of the two SNPs could decrease risk of CRC by 31 % (ORadj = 0.69, 95 % CI 0.53-0.91, p0.01) and 33 % (ORadj = 0.67, 95 % CI 0.47-0.95, p = 0.02), respectively. In addition, IVS7-212TA, IVS11+183AG and IVS8+719TC of hMSH2 were associated with the susceptibility to colon cancer rather than rectal cancer. ATTTGGGT and TCTTAGAC haplotypes were associated with 44 and 45 % decreased risk of CRC, respectively, while ATTTGAGT and TTTCAGAC haplotypes were associated with 1.37-fold and 2.49-fold increased risk of CRC, respectively. There was a significant three-way gene-gene interaction among hMSH2 IVS11+107AG, IVS11+183AG and IVS8+719TC (p0.01). Significant gene-environment interactions were observed between hMSH2 IVS15-214TC and IVS11+107AG and cereals consumption (both with p0.01).Our findings suggested that intronic SNPs, gene-gene and gene-environment interactions in hMSH2 might be associated with susceptibility to CRC.

Epilepsy is a type of chronic brain disease that results from an abnormally high synchronization of neuronal discharge. The typical clinical features of epilepsy are paroxysms and transient and stereotyped brain dysfunction. Many cases of epileptic seizures occurring during anesthesia have been reportedx. Recently, risk assessment of epileptic seizures during surgery and anesthesia has gained increasing attention. In this review, we systematically summarize the influence of anesthesia on epileptic seizures; the types, durations and frequencies of seizures related to anesthesia; and the epidemiology, prevention, treatment and prognosis of epilepsy. We also explore the possible mechanism of epilepsy and provide guidance for anesthesia during surgeries.

Salidroside, the important composition, of Rhodiola rosea L. has been reported to have various pharmacological properties. Liposome is known to be effective as drug carriers and immune adjuvant. Therefore, the aim of this study is to investigate immunological adjuvant activity of salidroside liposome. Here we reported the preparation, the effect on DCs in vitro and the immune response in vivo. The immunological adjuvant activity of salidroside liposome formulation was compared with that of salidroside and liposome. The result showed that salidroside liposome formulation not only could promote the maturation of DCs, the stimulation of DCs on MLR proliferation and the antigen presenting ability, but also induced the sustained cellular immune and humoral immune response. Overall, the results showed that salidroside liposome formulation had the potential to act as effective sustained release vaccine delivery systems.

The aim of this study is to investigate immunomodulatory effect of rehmannia glutinosa polysaccharide (RGP) on murine splenic lymphocyte and bone marrow derived dendritic cells (DCs). Splenic lymphocytes obtained from mice were co-cultured with RGP for 48 h and then harvested for analyzing with MTT method. The cytokine production of T lymphocytes was measured by ELISA. Effects of RGP treatment on DCs were investigated and assessed by MTT method. The results showed RGP significantly stimulated lymphocyte proliferation and the growth rate of T cell was more significant. The IL-2 and IFN-γ production of T lymphocyte were significantly upregulated after being stimulated with RGP. DCs stimulating on proliferation of T cells and the ability of antigen presenting of DCs have been enhanced under the stimulation of RGP. In conclusion, these findings provided valuable information that RGP possessed strong immunoenhancement activity, which provided the theoretical basis for the further experiment.

Cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LOX) and phospholipaseA2 (PLA2) played important roles in the modulation of apoptosis, angiogenesis, carcinogenesis and invasion of colorectal cancer (CRC). The polymorphisms in COX-2, 12-LOX and PLA2 may affect their roles. Therefore, we investigated if COX-2 −1195G > A, 12-LOX 261Arg > Gln and PLA2 c.349 + 191A > G polymorphisms were associated with risk and prognosis of CRC as well as possible interactions with the environmental factors on the risk of CRC in Northeast of China. A case–control study with 451 cases and 631 controls were carried out, a cohort with 386 patients were followed up. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Compared with the 261Arg/Arg genotype, 12-LOX 261Arg/Gln genotype and 261Arg/Gln + Gln/Gln genotypes reduced the risk of rectal cancer by 33 % (adjusted OR = 0.67, 95 % CI 0.47–0.97, p = 0.03) and 32 % (adjusted OR = 0.68, 95 % CI 0.49–0.96, p = 0.03), respectively. The adjusted HR for the association between 12-LOX 261Gln/Gln genotype and overall survival in patients with CRC was 1.68 (95 % CI 1.06–2.68, p = 0.03). There was also evidence of an interaction between the PLA2 c.349 + 191 A > G genotypes and the overnight food consumption (adjusted ORi = 1.92, 95 % CI 1.14–3.25, P interaction = 0.01). These observations indicate that 12-LOX 261Arg > Gln polymorphism may affect risk of rectal cancer, and it may be a potential predictive marker for prognosis of CRC.

Two hundred and fifty 11-day-old chickens were randomly assigned into 5 groups and except normal control group injected with cyclophosphamide once a day for 3 successive days. At day-14-old, all chickens were vaccinated with Newcastle disease vaccine. At the same time of the first vaccination, the chickens in three experimental groups were injected respectively with epimedium polysaccharide-propolis flavone immunopotentiator (EPI) at three dosages, once a day for 3 successive days. On days 7, 14, 21 and 28 after the first vaccination, the serum antibody titer and IgG, IgM, IFN-γ and IL-6 concentrations, peripheral lymphocyte proliferation, including immune organ index on day 28, were measured. The results demonstrated that EPI at high and medium doses could significantly enhance antibody titer and IgG, IgM, IFN-γ and IL-6 concentrations, promote lymphocyte proliferation and enlarge immune organ index as compared with model control group. This indicated that EPI could effectively resist the immunosuppression.

The purpose of this research was to compare the activities of different dose of epimedium polysaccharide-propolis flavone adjuvant (EPA). The inactivated avian influenza (AI) and Newcastle disease (ND) vaccine containing three doses of EPA were prepared. In AI vaccine vaccination experiment, 300 14-day-old chickens were randomly divided into 6 groups and inoculated with three EPA-AI vaccines taking oil adjuvant (OA), non-adjuvant (NA) vaccines and physiological saline as controls, repeated at 28-day-old. The lymphocyte proliferation and serum antibody titer were determined. In ND vaccine vaccination experiment, 300 14-day-old chickens were grouped, treated with three EPA-ND vaccines, and determined same to AI vaccine vaccination experiment; at 42-day-old the chickens were challenged with NDV. On D(15) after challenged, the immune protective effect was observed. The results showed that EPA could significantly promote lymphocyte proliferation and enhance serum antibody titer against AI and ND, and reduce the morbidity of chickens challenged with NDV after vaccinated with ND vaccine, especially the effect of medium dose was better than that of non-adjuvant and oil adjuvant. These results indicated that EPA could enhance the immune effect of inactivated AI vaccine and ND vaccine and would be expected as a new-type adjuvant.

Display Omitted A systematic profile of chemotherapeutic drug response to kinase gatekeeper mutation is created.The first-line therapy is found to cause acquired resistance upon the mutation.Staurosporine analog K252a is a good candidate for selectively targeting mutant over wild-type kinase.The mutation defines a number of additional noncovalent interactions at kinase-K252a interface. The epidermal growth factor receptor (EGFR) targeted therapy has been established as a routine strategy for treating non-small cell lung cancer (NSCLC). However, the gatekeeper mutation T790M in EGFR active site can confer generic resistance to tyrosine kinase inhibitors (TKIs), largely limiting the clinical applications of chemotherapeutic drugs in NSCLC. Here, a combined method of computational analysis and growth inhibition assay was described to systematically investigate the molecular response profile of wild-type-sparing and mutant-resistant inhibitors to the EGFR T790M mutation. The profile is highly consistent with previous clinical observations; three first-line chemotherapeutic drugs Gefitinib, Erlotinib and Lapatinib are established with acquired resistance upon the mutation. In addition, it was found that the alkaloid compound K252a, a Staurosporine analog isolated from Nocardiopisis sp., can selectively target the EGFR T790M mutant over wild-type kinase (23-fold selectivity), suggesting that the compound is good lead candidate for development of T790M mutant-selective inhibitors. Structural analysis revealed that the mutation-resulting Met790 residue does not induce steric hindrance to the EGFR T790M-K252a complex system, while a number of hydrophobic forces, van der Waals contacts and Sźπ interactions are observed between the aromatic rings of K252a and the sulfhydryl group of Met790, contributing considerable stabilization energy to the system.

The immunoenhancement of compound polysaccharides, APS-sEPS composed with astragalus polysaccharide (APS) and sulfated epimedium polysaccharide (sEPS), was observed in immunosuppressed model chicken induced by cyclophosphamide (Cy). 11-day-old chickens were injected with Cy once a day for three successive days except vaccine control group. At day-14-old, all chickens were vaccinated with ND vaccine, and in experimental groups simultaneously administrated with APS-sEPS at three dosages, APS and sEPS once a day for three successive days. On days 7, 14, 21 and 28 after the administration, the peripheral T-lymphocyte proliferation, serum antibody titers, IFN-γ, IL-2, IgG and IgM were determined. The results displayed that APS-sEPS could overcome Cy-induced immunosuppression, significantly promote T-lymphocyte proliferation and raised serum antibody titers, IFN-γ, IL-2, IgG and IgM levels, its high and medium doses were superior to single APS or sEPS. This demonstrated that APS and sEPS could synergistically resist the immunosuppression and APS-sEPS was an effective immunopotentiator.

Two experiments were carried out. In vitro, the effects of Astragalus polysaccharide liposome (APSL) on chicken's T and B lymphocytes proliferation were determined. The results showed that APSL could significantly promote T and B lymphocytes proliferation singly or synergistically with PHA and LPS and the efficacy were superior to those of Astragalus polysaccharide (APS) and blank liposome (BL) at most concentrations. In immune response experiment, the adjuvanticity of APSL at three doses, APS and BL were compared on chickens vaccinated with ND vaccine. The results showed that APSL could significantly promote lymphocyte proliferation, enhance antibody titer, promote IFN-γ, IL-2, IL-4 and IL-10 secretion, and its medium dose possessed the best efficacy. These results indicated that APSL could significantly improve the adjuvanticity and drug action of APS, and its medium dose possessed the best efficacy, the liposome would be expected to exploit into a new-type preparation of APS.

The aim of this strategy was to investigate whether the adjuvant activity of epimedium polysaccharide (EPS) could be further enhanced after encapsulated with liposome. In preparation of EPS liposome (EPSL) test, an orthogonal L9 (34) test design was used to optimize the preparation condition of EPSL. In adjuvant activity test, 350 14-day-old chickens were randomly assigned to 7 groups and vaccinated with Newcastle disease (ND) vaccine. Simultaneously, the chickens in experimental groups were injected with EPSL at three doses, EPS and blank liposome, respectively. The activity of lymphocytes proliferation, titer of serum antibody and concentrations of cytokines were determined. Results showed that the optimal preparation condition of EPSL was that ratio of drug to lipid, ratio of soybean phospholipid to cholesterol, ultrasonic time, and water bath temperature were 1:30, 4:1, 10 min and 40 °C, respectively. EPSL could significantly enhance the immune response of ND vaccine and promote cytokines secretion, and its high dose possessed the best efficacy. These findings indicated that liposome encapsulation could significantly improve the adjuvant activity of EPS.

Three preparations of epimedium polysaccharide-propolis flavone immunopotentiator (EPI), EPI liposome, EPI suspension and EPI watery solution were prepared. In immune response test, their adjuvanticities were compared in 14-day-old chickens vaccinated with Newcastle disease (ND) vaccine. In immune protection test, the effects of the three preparations on Newcastle disease virus (NDV) infection were compared in chickens vaccinated with ND vaccine then challenged with NDV. The results displayed that EPI liposome could enhance the antibody titer, T lymphocyte proliferation and the concentrations of interferon-γ and interleukin-6, when compared with the other two preparations. In EPI liposome group, the antibody titers, lymphocyte proliferation and protective rate were the highest, while the mortality and morbidity were the lowest, in comparison with the other groups. These results indicated that liposome could enhance the immune effect of EPI on ND vaccine and would be expected as the suitable dosage form of this immunopotentiator.

The aim of this study is to investigate whether the activity of inducing immune response of glycyrrhetinic acid (GA) could be enhanced after GA was encapsulated with liposome. Three hundred and fifty 14-day-old chickens were randomly assigned to 7 groups and vaccinated with Newcastle disease (ND) vaccine. Simultaneously, the chickens in experimental groups were injected with the glycyrrhetinic acid liposome (GAL) at three doses, GA and blank liposome, respectively. The activity of serum antibody titer, concentrations of immunoglobulins G (IgG) and immunoglobulins M (IgM), lymphocytes proliferation, the proportions of lymphocyte subpopulations (CD4(+) and CD8(+)) was determined after vaccination. GAL was evaluated for inducing humoral immunity and cellular immunity in chicken against Newcastle disease (ND) vaccine. The results showed that GAL not only could significantly enhance the antibody titers, IgG and IgM in ND vaccine immunized chicken, but also significantly promote the lymphocyte proliferation and the proportions of CD4(+) and CD8(+), as comparison with GA, BL and VC control groups. Moreover, the effects appear a dose-dependent manner and a time-dependent manner. These indicated that GAL could significantly promote the activation potential of humoral immunity and cellular immunity in chicken and present certain dose-effect and time-effect relationships. The formulations of GA and liposome can further enhance the immune response against ND vaccine compared with the adjuvant alone.

We report a typical case of hematidrosis in a Chinese girl who had experienced frequent bleeding episodes for more than 3 years. During hospitalization, spontaneous bleeding from her intact skin was witnessed by our staff on more than 20 occasions. Characteristically, bloody droplets from the intact skin contained all blood components. Histopathologic examination showed some inconspicuous abnormalities, with normal sweat gland structure containing no blood, and bloody exudate also came from some areas that do not contain sweat glands. We believe that the blood was mixed with a sweat-like fluid, rather than real sweat. The patient's bleeding problem was dramatically resolved by treatment with propranolol. We suggest that sympathetic nerve activation might play a role in these events, and that β-adrenoceptor antagonists might be an effective treatment for this disorder.

Summary. We studied two families in which the probands had severe bleeding tendency and showed low plasma levels of coagulation factor V (FV) antigen and activity. Sequence analysis of the FV gene on proband 1 demonstrated a novel G16088C homozygous missense mutation in exon 3 resulting in an Asp 68 to His substitution and on proband 2, a C69969T homozygous missense mutation in exon 23 leading to Gly2079Val. The parents of both families were each heterozygous for the corresponding FV gene defect. During their second pregnancy, the two families requested prenatal diagnosis. Chorionic villi were analysed at 12 weeks of gestation and cord blood samples were tested at 22 weeks. Microsatellite analysis performed in family 1 showed that the foetus sample was not contaminated by maternal tissue. The foetus 1 was found to be heterozygous for the familiar G16088C mutation with lower FV activity in the cord blood; the foetus 2 was a normal one. The diagnosis was confirmed after the birth. This is the first report of prenatal diagnosis for FV deficiency.

Here, we diagnosed a Turner syndrome patient complicated with well differentiated hepatocellular carcinoma. The patient had an extremely high level of plasma fibrinogen. However, her clinical features and coagulation test abnormalities were quite different from those reported cases. We investigated the mechanisms underlying the hyperfibrinogenemia and its effects on coagulation tests. Plasma fibrinogen was analyzed by Clauss, immunoturbidimetry and Western methods. The fibrinogen genes were sequenced. Activated partial thromboplastin time, prothrombin time and thrombin time were measured. Fibrinogen expression in tumor tissues was examined immunohistochemically. Plasma cortisone, interleukin 6 and soluble tissue factor were measured by immunoassays. We found that abundant fibrinogen protein was detected in tumor cells. Plasma fibrinogen activity and antigen were 14.4 +/- 0.8 and 15.1 +/- 0.3 g/l, respectively. On SDS-PAGE, patient and control fibrinogen subunits migrated similarly. No mutations were found in the fibrinogen genes. Activated partial thromboplastin time, prothrombin time and thrombin time were significantly prolonged, but were normalized when fibrinogen was partially absorbed by an antifibrinogen antibody. Plasma interleukin 6, cortisone and soluble tissue factor levels were increased as compared with those of controls. After tumor resection, plasma fibrinogen level and other laboratory tests returned to normal. Our results showed that the hyperfibrinogenemia was caused by hepatocellular carcinoma. High levels of plasma cortisone and interleukin 6 may also contribute to the hyperfibrinogenemia. With the increase of levels of plasma fibrinogen, the values of activated partial thromboplastin time, prothrombin time and thrombin time were gradually prolonged, probably due to the effect of fibrin on thrombin (antithrombin I) and restricted fibrin polymerization by superfluous fibrinogen.

Proteus syndrome is a rare hamartomous disorder with highly variable manifestations of disproportionate overgrowth of body parts, epidermal nevi and vascular malformations. We describe two patients who had typical clinical and imaging Proteus syndrome features. One of most characteristic findings in these two patients was that they had giant hemangiomas of the spleen that caused Kasabach-Merritt syndrome, demonstrating clinical bleeding and disseminated intravascular coagulation laboratory alterations. The present two cases are the first report of this complication in Proteus syndrome. The patients' bleeding tendency and hemostatic defects were completely corrected after they successfully underwent splenectomy.

We identified three novel mutations (p.Gly39Arg, p.Lys157Glu, p.Cys379Gly) and one previously known mutation (p.Asp141Asn) in the von Willebrand factor propeptide from three von Willebrand disease patients. All four mutations impaired multimerization of von Willebrand factor, due to reduced oxidoreductase activity of isomeric propeptide. These mutations resulted in the endothelial reticulum retention and impaired basal and stimulated secretions of von Willebrand factor. Our results support that the mutations in the D1 domain lead to defective multimerization, intracellular trafficking, and secretion of von Willebrand factor and result in bleeding of patients. Electronic supplementary material The online version of this article (doi:10.1186/s13045-015-0166-9) contains supplementary material, which is available to authorized users.