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OBJECTIVE: To study the expression level of plasma miR-106b-5p in primary immune thrombocytopenia (ITP) and its correlation with the levels of T helper 17 cell (Th17) and regulatory T cell (Treg) and the Th17/Treg ratio. METHODS: A total of 79 children with ITP (ITP group) and 40 healthy children (control group) were selected as subjects. According to the treatment response, the 79 children with ITP were divided into three groups: complete response (n=40), partial response (n=18), and non-response (n=21). Quantitative real-time PCR was used to measure the expression level of miR-106b-5p. Flow cytometry was used to measure the frequencies of Th17 and Treg, and the Th17/Treg ratio was calculated. The correlation of the expression level of plasma miR-106b-5p with the frequencies of Th17 and Treg and the Th17/Treg ratio was analyzed. RESULTS: Compared with the control group, the ITP group had significantly higher levels of miR-106b-5p, Th17, and Th17/Treg ratio (P

Ganoderic acids (GAs), a group of highly oxygenated lanostane-type triterpenoids from the traditional Chinese medicinal mushroom Ganoderma lucidum, possessed significant pharmacological activities. Due to the difficulty in its genetic manipulation, low yield, and slow growth of G. lucidum, biosynthesis of GAs in a heterologous host is a promising alternative for their efficient production. Heterologous production of a GA, 3-hydroxy-lanosta-8,24-dien-26-oic acid (HLDOA), was recently achieved by expressing CYP5150L8 from Ganoderma lucidum in Saccharomyces cerevisiae, but post-modification of HLDOA to biosynthesize other GAs remains unclear. In this study, another P450 from G. lucidum, CYP5139G1, was identified to be responsible for C-28 oxidation of HLDOA, resulting in the formation of a new GA 3,28-dihydroxy-lanosta-8,24-dien-26-oic acid (DHLDOA) by the engineered yeast, whose chemical structure was confirmed by UPLC-APCI-HRMS and NMR. In vitro enzymatic experiments confirmed the oxidation of HLDOA to DHLDOA by CYP5139G1. As the DHLDOA production was low (0.27 mg/L), to improve it, the strategy of adjusting the dosage of hygromycin and geneticin G418 to respectively manipulate the copy number of plasmids pRS425-Hyg-CYP5150L8-iGLCPR (harboring CYP5150L8, iGLCPR, and hygromycin-resistant gene hygR) and pRS426-KanMx-CYP5139G1 (harboring CYP5139G1 and G418-resistant gene KanMx) was adopted. Finally, 2.2 mg/L of DHLDOA was obtained, which was 8.2 fold of the control (without antibiotics addition). The work enriches the GA biosynthetic enzyme library, and is helpful to construct heterologous cell factories for other GA production as well as to elucidate the authentic GA biosynthetic pathway in G. lucidum. KEY POINTS: • Another P450 gene responsible for GA's post-modification was discovered and identified. • One new GA, DHLDOA, was identified and produced via engineered yeast. • With the balance of the two CYP genes expression, DHLDOA production was significantly improved.

The prognosis of acute myeloid leukemia (AML) is closely related to immune response changes. Further exploration of the pathobiology of AML focusing on immune-related genes would contribute to the development of more advanced evaluation and treatment strategies. In this study, we established a novel immune-17 signature based on transcriptome data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found that immune biology processes and transcriptional dysregulations are critical factors in the development of AML through enrichment analyses. We also formulated a prognostic model to predict the overall survival of AML patients by using LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Furthermore, we incorporated the immune-17 signature to improve the prognostic accuracy of the ELN2017 risk stratification system. We concluded that the immune-17 signature represents a novel useful model for evaluating AML survival outcomes and may be implemented to optimize treatment selection in the next future.

B lymphocyte-induced maturation protein-1 (Blimp-1) ensures B-cell differentiation into the plasma cell stage, and its instability constitutes a crucial oncogenic element in certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). However, the underlying degradation mechanisms and their possible therapeutic relevance remain unexplored. Here, we show that N-terminal misfolding mutations in ABC-DLBCL render Blimp-1 protein susceptible to proteasome-mediated degradation but spare its transcription-regulating activity. Mechanistically, whereas wild-type Blimp-1 metabolism is triggered in the nucleus through PML-mediated sumoylation, the degradation of lymphoma-associated mutants is accelerated by subversion of this pathway to Hrd1-mediated cytoplasmic sequestration and ubiquitination. Screening experiments identifies the heat shock protein 70 (HSP70) that selects Blimp-1 mutants for Hrd1 association, and HSP70 inhibition restores their nuclear accumulation and oncorepressor activities without disrupting normal B-cell maturation. Therefore, HSP70-Hrd1 axis represents a potential therapeutic target for restoring the oncorepressor activity of unstable lymphoma-associated Blimp-1 mutants., The transcriptional repressor Blimp-1 has an important role in B-cell differentiation. Here the authors show that lymphoma-associated Blimp-1 mutants are selectively recognized by HSP70-Hrd1, which leads to their accelerated degradation and propose HSP70 inhibition as a therapeutic approach for certain lymphomas.

Rosiglitazone (ROSI), an oral antidiabetic agent, has been reported the anti-cancer properties recent years. In this paper, the potency of ROSI as a synergistic drug for vincristine (VCR) on resistant oral cancer cells was investigated. We found that ROSI potently enhanced the susceptibility of KB cells or KB/V cells to VCR in a dose manner and the synergy in KB/V cells was much more prominent than that in KB cells. The synergistic anti-proliferative effect of ROSI and VCR was associated with inhibition on tubulin polymerization, cell cycle arrest in G2/M phase and cell apoptosis induction, but has no effect on drug efflux-protein P-gp and was independent with PPARγ. The combination treatment of ROSI and VCR could regulate the PTEN/PI3K/AKT survival pathway with an upregulation of PTEN and down-regulation of p-AKT. The effect of G2/M phase arrest was associated with the upregulation of cyclin B1 and downregulation of p-cdc2. The apoptosis induction of ROSI and VCR was partly due to an upregulation of cleaved PARP and downregulation of Bcl-2/Bax ratio. In addition, combination treatment of ROSI and VCR had also shown anti-angiogenic effect by suppressing the migration and blocking the capillary tube formation of HUVECs. More importantly, this combination treatment induced an acceptably weak cytotoxicity in human normal HL-7702 cells, GES-1 cells and HUVECs. Taken together, ROSI may be used as a potential compound for combinatorial therapy or as a complement to VCR for treatment on oral cancer, especially on that have acquired resistance to VCR therapy.

The nerve growth factor (NGF) is a growth factor that belongs to the neurotrophin family. NGF has two structurally different receptors, the p75 neurotrophin receptor (p75NTR) and the tropomyosin-related kinase A (TrkA). Interaction of NGF with its receptors regulates a variety of physiological processes of neuronal system. Recent studies have shown that NGF and its receptors were involved in the regulation of tumourigenesis by either supporting or suppressing tumor growth depending on the tumor types. This review summarizes the current views of NGF and its receptors in tumorigenesis and cancer pain.

We demonstrate the synergistic antitumor effect of oridonin and the PI3K/mTOR inhibitor NVP-BEZ235 on the non-germinal center B cell-like subtype of diffuse large B cell lymphoma (non-GCB DLBCL) both in vitro and in vivo. The underlying mechanism may be multifunctional, involving apoptosis, AKT/mTOR and NF-kB inactivation, and ROS-mediated DNA damage response. Our findings pave the way for a new potential treatment option for non-GCB DLBCL with the combination of oridonin and NVP-BEZ235. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0303-0) contains supplementary material, which is available to authorized users.

A village of Yubei, the typical area of north of Henan Province was selected. A field study was conducted in the traditional adobe house and newly built brick house, indoor and outdoor temperature, relative humidity and other indoor thermal environment parameters were obtained in winter. The results indicated that the indoor thermal environment in new and old folk houses were all lower than the local residential building thermal environment standard. Test data show that open the north door and one font design is the main reason leading to the adobe building indoor thermal environment is poor, and brick house around the main room layout features of "disposition" design is the main reason to maintain its good indoor thermal environment. The results provided the basis for the improvement of indoor thermal environment and the design of new residential buildings in this area, which provided the basis for the energy saving and sustainable development of rural residential buildings.

An enantioselective membrane was prepared using cellulose acetate as the membrane material. Cellulose acetate was chosen as it is in widespread use already for separations and cellulose triacetate is the first practical chiral stationary phase of polysaccharide due to the multichiral carbons in its molecular structure unit. The flux and permselective properties of a membrane was studied using a 33.3% ethanol solution of (R, S)-trans-stilbene oxide as the feed solution. The top surface and cross-section morphology of the resulting membrane were examined using scanning electron microscopy. An optical resolution of over 85% enantiomeric excess was achieved when the enantioselective membrane was prepared with 30 wt.% cellulose acetate and 25 wt.% N,N-dimethylformamide in the casting solution of acetone; 5 min was the time for evaporation of the liquid membrane, and a 10 °C water bath was used for the gelation of the membrane; the operating pressure and the feed concentration of the trans-stilbene oxide were 2 kgf/cm2 and 0.5 mg/L, respectively. This is the first report that cellulose acetate can be used as a membrane material for isolating optical isomers. This work indicates that the large-scale purification of chiral molecules from racemic mixtures will be realized by the enantioselective membrane technique in the near future and that the enantioselective cellulose acetate membrane could soon become very attractive for industrial uses.

As the cellulose acetate butyrate possessed multichiral carbon atoms in its molecular structure unit, enantioselective membrane was prepared using cellulose acetate butyrate as membrane material. The flux and permselective properties of membrane using aqueous solutions of ( R , S )-2-phenyl-1-propanol as feed solution was studied. The top surface and cross-section morphology of the resulting membranes were examined by scanning electron microscopy. When the membrane was prepared with 15 wt.% cellulose acetate butyrate and 20 wt.% DMF in the casting solution, and the operating pressure and feed concentration of racemate were 2 kgf/cm 2 and 5 mmol/L, respectively, over 98% of enantiomeric excess (e.e.) was obtained. This is a report, for the first time, that the cellulose acetate butyrate is used as optical resolution membrane material for isolating the optical isomers of ( R , S )-2-phenyl-1-propanol.

A ligustrazine (TMP) derivative, (E)-2-(2, 4-dimethoxystyryl)-3,5,6-trimethylpyrazine (DLJ14) was synthesized for the improvement of low bioavailability and short half-life of ligustrazine. We have observed potential reversal effects of DLJ14 on adriamycin (Adr)-resistant human myelogenous leukemia cells (K562/A02) and Adr-resistant human breast cancer cells (MCF-7/A) in vitro or in vivo in previous studies. The aim of the present study was to investigate the underlying molecular mechanism of DLJ14 and Adr combination treatment on Adr-resistant human breast cancer. Inhibition of cancer cell growth was estimated by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell cycle distribution was analyzed by flow cytometry and apoptosis determined using Annexin V-FITC/propidium iodide (PI) double staining and Hoechst 33258 nuclear staining. The expression of proteins in the epidermal growth factor receptor (EGFR)/phosphatidylinositol-3 kinase (PI3K)/Akt survival pathway and mitochondrial-mediated apoptosis pathway were measured by Western blotting analysis. Results showed that DLJ14 and Adr combination treatment exhibited stronger inhibition of the survival of MCF-7/A cells than Adr treatment alone. This effect might be associated with its role in cell cycle arrest and apoptosis induction. DLJ14 combined with Adr induced cell cycle arrest in the G2/M-phase by activating p21(wafl /cip1) and p53 in mitochondria and increased cleavage of caspase-9 and caspase-3, and Bax/Bcl-2 ratio. Mitochondrial membrane potential (MMP) disruption and cytochrome c (Cytc) release from mitochondria to cytosol suggested that apoptosis induction might be mediated by the mitochondrial pathway. Moreover, the combination of DLJ14 and Adr could down-regulate the expression of EGFR, p-EGFR, PI3K, and p-Akt in MCF-7/A cells. Overall, DLJ14 and Adr combination treatment may inhibit proliferation of Adr-resistant human breast cancer cells through inhibition of the EGFR/PI3K/Akt survival pathway and induction of apoptosis via the mitochondrial-mediated apoptosis pathway.

The incidence of osteosarcoma is increased 500-fold in patients who inherit mutations in the RB gene. To understand why the retinoblastoma protein (pRb) is specifically targeted in osteosarcoma, we studied its function in osteogenesis. Loss of pRb but not p107 or p130 blocks late osteoblast differentiation. pRb physically interacts with the osteoblast transcription factor, CBFA1, and associates with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of pRb with CBFA1 and promoter sequences results in synergistic transactivation of an osteoblast-specific reporter. This transactivation function is lost in tumor-derived pRb mutants, underscoring a potential role in tumor suppression. Thus, pRb functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of pRb in osteosarcoma.

Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma and accounts for approximately 30 % of newly diagnosed lymphoid neoplasms in Western countries, and 40–50 % in China. A better understanding of the biology of DLBCL is needed for the development of potential therapeutic agents that target specific intracellular pathways. In this study, expression of the important components of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and their clinical significance were investigated in 73 DLBCL cases. The effect of rituximab alone or combined with the PI3K/AKT/mTOR pathway inhibitor rapamycin was further evaluated in the DLBCL cell lines. A total of 73 patients were identified, including 45 men and 28 women aged 18 to 78 years (median age 50 years). Of these patients, p-AKT was positive in 40 cases (54.8 %), p-p70S6K in 34 cases (46.6 %), and p-4E-BP1 in 33 cases (45.2 %). Activation of the PI3K/AKT/mTOR pathway was related to poor disease outcome in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) but not in those treated with rituximab-CHOP. Rituximab combined with rapamycin synergically downregulated the PI3K/AKT/mTOR signaling pathway. Western blot analysis revealed a baseline activation status of the PI3K/AKT/mTOR pathway in DLBCL cell lines, with high levels of p-AKT, p-mTOR, in addition to downstream molecules p-p70S6K and p-4E-BP1. The results indicate that the PI3K/AKT/mTOR pathway is a potentially important signaling route and an unfavorable prognostic factor for DLBCL. Patients with PI3K/AKT/mTOR activation experience a more rapidly deteriorating clinical course with poor treatment response and decreased survival time. Addition of rituximab could downregulate PI3K/AKT/mTOR activation, reversing its negative effect on chemotherapy-treated patients. In addition, our results indicate that the combination of rituximab and inhibition of the activated PI3K/AKT/mTOR pathway could be a promising target for DLBCL therapeutic intervention in the future.

This paper presents New Open Economy Macroeconomics as the analytical framework in attempt to explore the long term effects of fiscal expenditure shocks on various macroeconomic variables (e.g. consumption, output, prices, exchange rate, terms of trade), and tries to explain the role that consumption home bias plays. With theoretical derivation and simulation analysis, we find that in the long-term, an increasing in fiscal spending will cause rise of domestic output, domestic price index and the exchange rate, but it will crowd out domestic private consumption, the relationship between fiscal spending and the terms of trade, which is depending on asymmetry of consumption bias behavior of consumers between countries.

To the Editor: Spinocerebellar ataxia (SCA) is an inherited disorder of brain function characterized by progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. It is a slowly progressive disease that gradually worsens over a period of years. Zolpidem is a nonbenzodiazepine sedative in the imidazopyridine class and is chemically distinct from other sedatives. It is a short-acting hypnotic with a selective agonist effect for γ-aminobutyric acid (GABA) type A receptors in the brain. It was considered originally by physicians as almost devoid of abuse and dependence potential. Intriguingly, aside from its hypnotic effect, zolpidem has been shown to improve catatonia,1 aphasia,2 Parkinson's disease,3 and ataxia.4 However, reports of zolpidem abuse or dependence are increasing,5,6 and more attention should be paid in terms of zolpidem withdrawal. We report a patient with SCA who took zolpidem for movement difficulties initially, developed dependence on high-dose zolpidem treatment, and encountered serious withdrawal symptoms. We also review the literature on the possible mechanism for the effect of zolpidem on SCA. Case report. Ms A, a 40-year-old married woman, was referred in 2009 for psychiatric consultation due to high-dose zolpidem use. She was diagnosed with SCA type IV at age 35 years with initial symptoms of unsteady gait and mild slurred speech. Her father and brother were also afflicted with SCA. This time, she was admitted via emergency department to our neurology department because of loss of consciousness. Generalized seizure lasted for 1 minute at home, and initial management at the emergency department with phenytoin intravenous drip terminated further progression. Toxicology testing detected no plasma alcohol, whereas plasma benzodiazepine level was 64.80 ng/mL. She claimed she had abused triazolam and alcohol during early adulthood due to insomnia. Other illicit substance use was denied. She had started taking zolpidem 3 years earlier for insomnia, and, paradoxically, zolpidem relieved her ataxia and spasticity. She recalled being able to move her arms and turn her trunk more easily, although the improvement lasted only around 1 hour after taking zolpidem. The dose of zolpidem was gradually escalated by the patient to reach optimal effect. The dose usually amounted to 1,000 mg/d for the past year. Nausea, palpitation, jitters, hand tremor, and perspiration were noted if she did not take enough zolpidem. She was bedridden due to SCA and was cared for by her husband. Although she consumed high doses of zolpidem, her husband tried to cater to all her needs out of sympathy. Zolpidem had been prescribed from different physicians. Withdrawal seizures were noted several times if her supply of zolpidem fell short. Ms A was detoxified by taper of zolpidem gradually over 2 weeks. We prescribed trazodone 100 mg before sleep and diazepam 20 mg/d and propranolol 30 mg/d for anxiety. No seizure attack was noted during hospitalization. After this 2-week hospitalization, she was referred to the psychiatric clinic for further management. The imidazopyridine hypnotic zolpidem binds preferably to the α1 subtype of the benzodiazepine receptor, which is part of GABAA receptor complex. This highly accounts for its sedative effect, whereas the anxiolytic action of benzodiazepines appears to be mediated by receptors that contain the α2 subunit.7 Zolpidem at high doses might lose its selectivity on α1 subunits and bind to lower-affinity α2 units, leading to an anxiolytic effect. Thus, high-dose zolpidem may have a paradoxical effect for alleviating anxiety, and abrupt discontinuation would produce withdrawal symptoms such as palpitation, anxiety, tremor, or seizure similar to those seen with benzodiazepine withdrawal. There is no definite treatment that can prevent or slow the progression of SCA. Clauss et al4 reported transient improvement of SCA with zolpidem in 4 cases. Single photon emission computed tomography demonstrated that GABAergic function may be decreased in the cerebral cortex, thalamus, striatum, and cerebellum in patients with SCA.8 Zolpidem has been shown to mildly improve catatonia, aphasia, and Parkinson's disease.9 Such motor improvement may be due to selective inhibition by zolpidem of GABAergic inhibitory neurons in the internal globus pallidus and substantia nigra pars reticulata, resulting in activation of the thalamus and cerebral cortex.9 Positron emission tomography imaging also has shown normalized tracer uptake in the left thalamus and cerebellum after treatment with zolpidem.4 Our case further corroborates that zolpidem has a mode of action apart from hypnotic properties. To our knowledge, this is the first case report concerning high-dose zolpidem withdrawal seizure in a patient with SCA. We should be more cautious in prescribing zolpidem to patients with past drug abuse or dependence to prevent unwanted consequence. Further investigation of the pharmacologic efficacy of zolpidem in SCA might be needed.

International audience; Dynamic Epistemic Logic (DEL) can model complex information scenarios in a way that appeals to logicians. However, existing DEL implementations are ad-hoc, so we do not know how the framework really performs. For this purpose, we want to hook up with the best available model-checking and SAT techniques in computational logic. We do this by first providing a bridge: a new faithful representation of DEL models as so-called knowledge structures that allow for symbolic model checking. Next, we show that we can now solve well-known benchmark problems in epistemic scenarios much faster than with existing DEL methods. Finally, we show that our method is not just a matter of implementation, but that it raises significant issues about logical representation and update.