Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple-Negative Breast Cancer.

As a critical epigenetic modulator of gene expression, histone deacetylases (HDACs) have been involved in the pathogenesis and therapeutic investigation of cancer. Quinolizidine alkaloid sophoridine is known to have anticancer efficacy but with limited indication. By incorporating the pharmacophore of the HDAC inhibitor into the ring-opened sophoridine core, a new series of sophoridine hydroxamic acid derivatives were synthesized. After structure-activity studies, a selected compound was found to exert significant cytotoxicity in triple-negative breast cancer CAL-51 cells (IC50 1.17 µM), and demonstrated low nanomolar inhibitory potency toward HDAC1/3/6. Cellular functional assays indicated that this compound was able to induce apoptosis and cause accumulation of cells in the S phase of the cell cycle. Western blot analysis revealed it to decrease the expression of DNMT1, DNMT3a and DNMT3b by down-regulating phosphor-ERK1/2. Furthermore, treatment with this compound proved to block the PI3K/AKT/mTOR signaling in the PI3KCA and PTEN-mutant CAL-51 cells. Collectively, this work provides a novel lead compound for the development of potential therapeutics against triple-negative breast cancers, possibly mesenchymal-like subtype.

Predicting Blood-Brain Barrier Permeation of Erlotinib and JCN037 by Molecular Simulation.

Glioblastoma (GBM) is a highly malignant primary brain tumor, and epidermal growth factor receptor (EGFR) is a well characterized biomaker on GBM. Treatment of GBM with EGFR inhibitors achieved limited efficacy due to low blood-brain barrier (BBB) permeability, and BBB-penetrant drugs are required. In this study, the BBB penetration of erlotinib and JN037 were studied using molecular dynamics method with explicit membrane model. The free energy profiles indicate that JCN037 has a lower central energy barrier than erlotinib, and it has a local minimum at lipid-water interface while erlotinib has not. Unconstrained MD simulations found that erlotinib prefers staying in water while JCN037 tends to interact with lipid molecules. Further analysis reveals that the Br atom of JCN037 plays an important role in its interaction with lipid molecules, and the adjacent F atom enhances the interaction of Br. The two flexible methoxyethoxy chains of erlotinib are responsible for its poor penetration. Our computational results agree well with the experimental results, providing useful information in the design and improvement of drugs with good BBB permeation.

Nomogram for Prediction of Postoperative Delirium after Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease under General Anesthesia.

Introduction: Postoperative delirium can increase cognitive impairment and mortality in patients with Parkinson's disease. The purpose of this study was to develop and internally validate a clinical prediction model of delirium after deep brain stimulation of the subthalamic nucleus in Parkinson's disease under general anesthesia. Methods: We conducted a retrospective observational cohort study on the data of 240 patients with Parkinson's disease who underwent deep brain stimulation of the subthalamic nucleus under general anesthesia. Demographic characteristics, clinical evaluation, imaging data, laboratory data, and surgical anesthesia information were collected. Multivariate logistic regression was used to develop the prediction model for postoperative delirium. Results: A total of 159 patients were included in the cohort, of which 38 (23.90%) had postoperative delirium. Smoking (OR 4.51, 95% CI 1.56-13.02, p < 0.01) was the most important risk factor; other independent predictors were orthostatic hypotension (OR 3.42, 95% CI 0.90-13.06, p=0.07), inhibitors of type-B monoamine oxidase (OR 3.07, 95% CI 1.17-8.04, p=0.02), preoperative MRI with silent brain ischemia or infarction (OR 2.36, 95% CI 0.90-6.14, p=0.08), Hamilton anxiety scale score (OR 2.12, 95% CI 1.28-3.50, p < 0.01), and apolipoprotein E level in plasma (OR 1.48, 95% CI 0.95-2.29, p=0.08). The area under the receiver operating characteristic curve (AUC) was 0.76 (95% CI 0.66-0.86). A nomogram was established and showed good calibration and clinical predictive capacity. After bootstrap for internal verification, the AUC was 0.74 (95% CI 0.66-0.83). Conclusion: This study provides evidence for the independent inducing factors of delirium after deep brain stimulation of the subthalamic nucleus in Parkinson's disease under general anesthesia. By predicting the development of delirium, our model may identify high-risk groups that can benefit from early or preventive intervention.

Identification of candidate miRNA biomarkers correlated with the prognosis of cell carcinoma and endocervical adenocarcinoma via integrated bioinformatics analysis.

OBJECTIVES: This study was designed to explore MicroRNAs (miRNAs) associated with the prognosis of cell carcinoma and endocervical adenocarcinoma (CESC) to search for biomarkers of CESC and provide guidelines for the clinical treatment. METHODS: mRNAs of CESC patients were downloaded from The Cancer Genome Atlas (TCGA), and miRNA expression and clinical data of the patients were preprocessed. Key miRNAs associated with the prognosis of cervical cancer were identified by weighted gene co-expression network (WGCNA). The corresponding target genes were intersected with differentially expressed genes (DEGs) acquired from variation analysis, and the pathways and functional enrichment of genes were analyzed. Key genes were screened by Kaplan-Meier (K-M) survival analysis. Risk models were constructed using Cox proportional hazard regression model and the Least Absolute Shrinkage and Selection Operator (LASSO) method, and the predictive value of the models was evaluated by time-associated receiver operating characteristic (ROC) curves. Finally, independent prognostic factors were identified by COX analysis. RESULTS: The hsa-miR-3150b-3p associated with the prognosis of CESC was identified by WGCNA. A total of 136 target genes were differentially expressed in CESC tissue and were associated with biological processes such as phylogeny, multicellular organism development and cell development. CBX7, ENPEP, FAIM2, IGF1, NUP62CL and TSC22D3 were associated with the prognosis of CESC, and a prognostic prediction model was constructed using these six genes, which had a good predictive value for the prognosis of cervical cancer within 1, 3 and 5 years (AUC: 0.784, 0.680 and 0.683, respectively). Among them, ENPEP (hazard ratio = 1.3996, 95% confidence interval: 1.0552-1.8565) was identified as an independent prognostic factor. CONCLUSIONS: In this study, a highly accurate prognostic model consisting of six gene signatures was developed to predict the prognosis of patients with cervical cancer, which provides a reference for developing individualized treatment plans for patients.

Synthesis and biological evaluation of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl)glycines as oral erythropoietin secretagogues.

Erythropoietin (EPO) is the predominant regulating factor in erythropoiesis. Herein we describe the identification of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl) glycine-based oral EPO secretagogues. Most of these compounds obviously increased the EPO level in Hep3B cells by stabilizing the hypoxia-inducible factor-α (HIF-α). Furthermore, their potential inhibitory activities against HIF prolyl hydroxylase domain (PHD) revealed their function as PHD inhibitors in PHD-HIF pathway. Compound 6i, with a biphenyl substituent on the sulfonamido group, particularly increased plasma EPO level in mice and could serve as a candidate of EPO stimulating agent for anemia treatment.

Molecular dynamics simulations of a central nervous system-penetrant drug AZD3759 with lipid bilayer.

AZD3759 is an epidermal growth factor receptor inhibitor with good blood-brain barrier permeability, demonstrating encouraging activity against central nervous system metastases. However, the underlying mechanism was still unclear. In this study, the interaction between AZD3759 and membrane was studied with 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayer as a model lipid. Both the cationic and neutral state of AZD3759 were considered in the simulations, and the results show that cationic AZD3759 forms more hydrogen bonds with bilayer than neutral AZD3759, and Coulombic interaction has great effects in the transmembrane process of cationic AZD3759. AZD3759 prefers to reside in the interface between the hydrophilic headgroup region and hydrophobic region of bilayer, and the chloroflurobenzene moiety plays a crucial role in the insertion of AZD3759. PMF results suggest that the hydrophobic region of DMPC bilayer is permeable by AZD3759. Understanding the transmembrane mechanism of AZD3759 at molecular level may provide useful information to the design and optimization of anti-tumor drugs with improved BBB penetration. • The penetration mechanism of AZD3759 with DMPC bilayer was studied by molecular dynamics simulations. • Neutral AZD3759 could penetrate deeper into DMPC bilayer than protonated AZD3759. • The chloroflurobenzene moiety plays a significant role in the insertion of AZD3759 into DMPC bilayer. • The electrostatic interaction is the driving force for the initial binding of AZD3759 to DMPC bilayer. • Our findings may enhance the mechanism understanding of drugs with good BBB permeability.

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple-Negative Breast Cancer through Inhibition of mTOR Signaling.

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.

LncRNA-ROR/microRNA-185-3p/YAP1 axis exerts function in biological characteristics of osteosarcoma cells.

AIM: The co-expression network of long non-coding RNA ROR (lncRNA-ROR) and microRNA-185-3p (miR-185-3p) has not been focused on osteosarcoma. Therein, this work was initiated to uncover lncRNA-ROR and miR-185-3p functions in osteosarcoma. METHODS: LncRNA-ROR, miR-185-3p and Yes-associated protein 1 (YAP1) expression in osteosarcoma tissues and cells were detected. The screened cells (MG63 and U2OS) were transfected with decreased and/or increased lncRNA-ROR and miR-185-3p to explore osteosarcoma progression. Tumor growth was detected by tumor xenografts in mice. RESULTS: Up-regulated lncRNA-ROR and YAP1 and down-regulated miR-185-3p were found in osteosarcoma. LncRNA ROR knockdown or miR-185-3p overexpression inhibited osteosarcoma cell progression while lncRNA ROR elevation or miR-185-3p inhibition presented the opposite effects. Function of lncRNA ROR was rescued by miR-185-3p and regulated the growth and metastasis of osteosarcoma cells via modulating YAP1, the target gene of miR-185-3p. CONCLUSION: This work illustrates that lncRNA-ROR down-regulation or miR-185-3p up-regulation inhibits osteosarcoma progression via YAP1 repression.

lncRNA Xist Regulates Osteoblast Differentiation by Sponging miR-19a-3p in Aging-induced Osteoporosis.

The switch between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) plays a key role in aging-induced osteoporosis. In this study, miR-19a-3p was obviously downregulated in BMSCs from aged humans and mice. Overexpressed miR-19a-3p evidently reduced aging-induced bone loss in mice and promoted osteogenic differentiation of BMSCs, while silenced miR-19a-3p manifestly increased aging-induced bone loss in mice and repressed osteogenic differentiation of BMSCs. Hoxa5 was significantly downregulated in the BMSCs from aged mice and contribute to miR-19a-3p-induced osteoblast differentiation as a direct target gene of miR-19a-3p. Furthermore, lncRNA Xist was found as a sponge of miR-19a-3p to repress BMSCs osteogenic differentiation. In conclusion, our study reveals the critical role of the lncRNA Xist/miR-19a-3p/Hoxa5 pathway in aging-induced osteogenic differentiation of BMSCs, indicating the potential therapeutic target for osteoporosis.

WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner.

N6-methyladenosine (m6A) regulators are involved in the progression of various cancers via regulating m6A modification. However, the potential role and mechanism of the m6A modification in osteosarcoma remains obscure. In this study, WTAP was found to be highly expressed in osteosarcoma tissue and it was an independent prognostic factor for overall survival in osteosarcoma. Functionally, WTAP, as an oncogene, was involved in the proliferation and metastasis of osteosarcoma in vitro and vivo. Mechanistically, M6A dot blot, RNA-seq and MeRIP-seq, MeRIP-qRT-PCR and luciferase reporter assays showed that HMBOX1 was identified as the target gene of WTAP, which regulated HMBOX1 stability depending on m6A modification at the 3'UTR of HMBOX1 mRNA. In addition, HMBOX1 expression was downregulated in osteosarcoma and was an independent prognostic factor for overall survival in osteosarcoma patients. Silenced HMBOX1 evidently attenuated shWTAP-mediated suppression on osteosarcoma growth and metastasis in vivo and vitro. Finally, WTAP/HMBOX1 regulated osteosarcoma growth and metastasis via PI3K/AKT pathway. In conclusion, this study demonstrated the critical role of the WTAP-mediated m6A modification in the progression of osteosarcoma, which could provide novel insights into osteosarcoma treatment.

Differences in pathologic characteristics between ductal carcinoma in situ (DCIS), DCIS with microinvasion and DCIS with invasive ductal carcinoma.

In order to further our understanding of pathologic features in various ductal carcinoma in situ (DCIS) related breast ductal cancers, including DCIS, DCIS with microinvasion (DCIS-Mi) and DCIS with invasive ductal carcinoma (DCIS-IDC), a retrospective study including 453 cases of DCIS, 88 cases of DCIS-Mi, and 269 cases of DCIS-IDC was conducted. Statistical analysis showed significant pathological differences were found in DCIS, DCIS-Mi, and DCIS-IDC. Compared with DCIS, DCIS-IDC was significantly more associated with high nuclear grade, large tumor size, high Ki67 index, and lymph node metastasis (all P<0.05). Higher expression of steroid receptors was shown in DCIS-IDC than in DCIS (all P<0.05), but the status of HER2 between the two groups was similar (P=0.269). Compared with DCIS, DCIS-Mi was significantly more associated with high nuclear grade, large tumor size, comedonecrosis, absence of steroid receptors, HER2 overexpression, and high Ki67 index (all P<0.05). These features remain consistently even when compared with DCIS-IDC. According to the immunohistochemistry surrogate classification, the dominant types of DCIS and DCIS-IDC were luminal types (luminal A and luminal B, respectively), while the dominant type of DCIS-Mi was HER2 overexpression. These findings suggest that DCIS-Mi represents a distinct entity, and DCIS with features including high nuclear grade, large tumor size, comedonecrosis, steroid receptors negativity, HER2 positivity, and high Ki67 expression was more likely to have microinvasion than DCIS without these features.

Novel Copper Complexes That Inhibit the Proteasome and Trigger Apoptosis in Triple-Negative Breast Cancer Cells.

Five innovative ternary copper(II) complexes [Cu(OH-PIP)(Phe)Cl](1), [Cu(OH-PIP)(Gly)(H2O)]NO3·2H2O (2), [Cu(OH-PIP)(Ala)(Cl)]·H2O (3), [Cu(OH-PIP)(Met)]PF6·2H2O (4), and [Cu(OH-PIP)(Gln)(H2O)](Cl)·3H2O (5) have been synthesized and characterized by infrared spectroscopy, elemental analysis, and single crystal X-ray diffraction analysis. X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration. The complexes have been screened for cytotoxicity against human breast cancer cell lines MCF-7, MDA-MB-231, and CAL-51. The best anticancer activity is obtained with triple-negative breast cancer CAL-51 and MDA-MB-231 cell lines, with IC50 values in the range of 0.082-0.69 µM. Importantly, the copper compounds were more effective than carboplatin at triggering cell death. Mechanistically, the complexes inhibit proteasomal chymotrypsin-like activity, and docking studies reveal their 20S proteasome binding sites. As a consequence, they cause the accumulation of ubiquitinated proteins, inhibit cell proliferation, and induce apoptosis. In addition, these copper complexes decrease the stemness of triple-negative breast cancer cells and have synergistic effects with CBP on TNBC cells, indicating their great potential as a novel therapy for triple-negative breast cancer.

Novel Sophoridine Derivatives Bearing Phosphoramide Mustard Moiety Exhibit Potent Antitumor Activities In Vitro and In Vivo.

Novel mustard functionalized sophoridine derivatives were synthesized and evaluated for their cytotoxicity against of a panel of various cancer cell lines. They were shown to be more sensitive to S180 and H22 tumor cells with IC50 values ranging from 1.01⁻3.65 µM, and distinctly were more cytotoxic to cancer cells than normal cell L929. In addition, compounds 7a, 7c, and 7e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Furthermore, they arrested tumor cells in the G1 phase and induced cellular apoptosis. Their potential binding modes with DNA-Top I complex have also been investigated.

Isolation and characterization of a novel chalcone synthase gene family from mulberry.

Chalcone synthase (CHS) is the pivotal enzyme that catalyzes the first committed step of the phenylpropanoid pathway leading to flavonoids. Here, five CHS genes were determined in mulberry (Morus atropurpurea Roxb.). Interestingly, phylogenetic analysis tended to group three MaCHSs in the stilbene synthase (STS) family and initially annotated these as MaSTSs. A co-expression system that harbored a 4-coumarate:CoA ligase gene and one of the candidate genes was established to determine the functions of this novel gene family. The fermentation result demonstrated that MaSTS in fact encoded a CHS enzyme, and was consequently retermed MaCHS. Tissue-specific expression analysis indicated that MaCHS1/MaCHS2 was highly abundant in fruit, and MaCHS4 had significant expression in root bark, stem bark and old leaves, while MaCHS3 and MaCHS5 were more expressed in old leaves. Subcellular localization experiments showed that MaCHS was localized to the cytoplasm. Transcription levels suggested MaCHS genes were involved in a series of defense responses. Over-expression of MaCHS in transgenic tobacco modified the metabolite profile, and resulted in elevated tolerance to a series of environmental stresses. This study comprehensively evaluated the function of MaCHS genes and laid the foundation for future research on MaCHS in mulberry.

Characterization of Stilbene Synthase Genes in Mulberry (Morus atropurpurea) and Metabolic Engineering for the Production of Resveratrol in Escherichia coli.

Stilbenes have been recognized for their beneficial physiological effects on human health. Stilbene synthase (STS) is the key enzyme of resveratrol biosynthesis and has been studied in numerous plants. Here, four MaSTS genes were isolated and identified in mulberry (Morus atropurpurea Roxb.). The expression levels of MaSTS genes and the accumulation of trans-resveratrol, trans-oxyresveratrol, and trans-mulberroside A were investigated in different plant organs. A novel coexpression system that harbored 4-coumarate:CoA ligase gene (Ma4CL) and MaSTS was established. Stress tests suggested that MaSTS genes participate in responses to salicylic acid, abscisic acid, wounding, and NaCl stresses. Additionally, overexpressed MaSTS in transgenic tobacco elevated the trans-resveratrol level and increased tolerance to drought and salinity stresses. These results revealed the major MaSTS gene, and we evaluated its function in mulberry, laying the foundation for future research on stilbene metabolic pathways in mulberry.

Association between the rs11614913 variant of miRNA-196a-2 and the risk of epithelial ovarian cancer.

Polymorphisms in microRNA (miR) genes and their target sites are a distinct classification of variation in the human genome, which are rapidly being identified and investigated in human cancer. A polymorphism in the miR-196a-2 locus has demonstrated significant associations with various types of cancer, including lung, breast, esophageal and gastric tumors. However, miR-196a-2 has not been fully explored in ovarian cancer, which shares similar biological characteristics with other types of cancer. Therefore, the present study aimed to elucidate the association between a single nucleotide polymorphism (SNP) in the mature sequence of miR-196a-2 (rs11614913, T/C) and the clinical features of 479 Chinese patients with epithelial ovarian cancer (EOC). In addition, the biological significance of this polymorphism was investigated in the OVCAR3 ovarian cancer cell line. Risk association was evaluated in 479 cases of EOC patients and 431 controls. SNPs were analyzed by using polymerase chain reaction based restriction fragment length polymorphism assay. miR-196a expression was evaluated with reverse transcription polymerase chain reaction. The influence of miR-196a-2 rs11614913 T/C on EOC cell migration and invasion ability was further investigated in vitro. The results revealed significant differences in the homozygous CC genotype distribution in patients with EOC (n=479), compared with that of the control subjects (n=431; P=0.026). Analysis of the association between genotype and the risk of EOC revealed that individuals who carried the homozygous CC genotype were 1.34-fold more susceptible to EOC, compared with those carrying the wild-type TT and heterozygous CT genotypes [odds ratio, 1.34; 95% confidence interval, 1.04-2.17; P=0.023]. In addition, the role of this polymorphism in the production of mature miR-196a was investigated. Significantly enhanced production of mature miR-196a was revealed in the C-allelic compared with that of the T-allelic miR-196a-2 precursor (P<0.05). Further examination indicated that miR-196a significantly promoted cell migration and invasion ability in the human OVCAR3 ovarian cell line (P<0.05). In conclusion, the results indicated that the miR-196a-2 rs11614913 CC genotype may increase the risks of ovarian cancer by affecting the expression of mature miR-196a and enhancing cell migration/invasion. The current results provided evidence that the T>C polymorphism in the miR-196a-2 precursor may influence tumorigenesis and metastasis in EOC, and suggested that the functional SNP rs11614913 in the promoter region of pri-miR-196a-2 may be a potential indicator of EOC susceptibility in the population analyzed.

[Efficacy of the Sentinel Mouse Method in Monitoring Schistosoma japonicum Infection in Key #br# Water Areas of Hanchuan City].

Objective: To understand the water infectivity of schistosomes in key water areas of Hanchuan City, and explore the use of sentinel mice in surveillance and forecast of schistosomiasis. Methods: Surveillance and forecast sites were set up in North Han River, Diaocha Lake, and Miaowu Ditch in 2014. Sentinel mice （male Kunming mice, n=20 in each site） were placed there within the first ten-day period of June and September, respectively. Field detections lasted 4 h each, for a total of 2 days. The loss and death rates of mice were recorded. Humans and livestocks with activities in these sites were also examined for schistosome infection. The sentinel mice recovered were raised in laboratory for 35 days, dissected, and examined for liver granulomas and adult worm counting. The distribution of sites with positive detections and their infection status were analyzed. Emergency measures were taken in the positive sites. Results: A total of 13（5 sites in North Han River, 5 in Diaocha Lake, and 3 in Miaowu Ditch） surveillance and forecast sites were set up. No infected snail was detected in any of these sites in spring 2014. The detection rate of living snails in North Han River （18.7%, 224/1 201) was significantly higher than that in Diaocha Lake（12.8%, 852/6 644） and in Miaowu Ditch （6.4%, 202/3 147）（P<0.01）. Of the 520 mice placed, 6 were lost, and 514 were recovered, among which 4 mice died during laboratory raising. The remaining 510 sentinel mice were then dissected, revealing infection in 4 mice, with a positive rate of 0.8%. Twenty-seven Schistosoma japonicum worms were collected, and the mean worm burden of positive mice was 6.8 worms per mouse. Three sites (Sansi village, Kangjia village and Doubu village) were found to be positive sites of infection in September, with the detailed number of 2, 1 and 0 in North Han River, Diaocha Lake, and Miaowu Ditch respectively, with a positive rate of 1.5% （3/197）, 0.5% （1/195） and 0 （0/118） in sentinel mice （P>0.05）. In addition, among the 22 cattle found in the 13 sites, 2 were infected with schistosomes; and among the 62 fishermen and boatmen, 2 were infected. Emergency measures were taken in the three positive sites, and no high endemicity occurred. Conclusion: The monitoring of sentinel mice infections can improve the sensitivity of the surveillance and forecast system of schistosomiasis. The infected fishermen and cattle remain the major source of schistosomiasis transmission in Hanchuan City.

Risk factors for hypothermia in patients under general anesthesia: Is there a drawback of laminar airflow operating rooms? A prospective cohort study.

INTRODUCTION: The aim of this study was to estimate the prevalence and risk factors of hypothermia under general anesthesia in a large domestic hospital. METHOD: All of the consecutive 1840 patients who underwent scheduled surgery between August and December 2013 were admitted to the study. The nasopharyngeal temperature was measured, and the following variables were also recorded: sex, age, type of surgery, duration of anesthesia, active warming devices and type of operating room. Univariate and multiple regression binary logistic analyses with odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the relationship between each clinical risk factor and hypothermia. RESULTS: The prevalence of hypothermia under general anesthesia was 25.7%. In the univariate analysis, the risk factors of hypothermia were age, the duration of anesthesia, the type of operating room and the type of surgery. Sex was not included. In the multiple logistic regression analysis, the significant risk factors of hypothermia were advanced age, laminar airflow operating rooms and general surgeries. CONCLUSION: Intraoperative hypothermia is still common and should therefore receive serious attention. Advanced age, the use of a laminar airflow operating room and general surgeries are high risk factors of hypothermia.

Far-field subwavelength imaging with near-field resonant metalens scanning at microwave frequencies.

A method for far-field subwavelength imaging at microwave frequencies using near-field resonant metalens scanning is proposed. The resonant metalens is composed of switchable split-ring resonators (SRRs). The on-SRR has a strong magnetic coupling ability and can convert evanescent waves into propagating waves using the localized resonant modes. In contrast, the off-SRR cannot achieve an effective conversion. By changing the switch status of each cell, we can obtain position information regarding the subwavelength source targets from the far field. Because the spatial response and Green's function do not need to be measured and evaluated and only a narrow frequency band is required for the entire imaging process, this method is convenient and adaptable to various environment. This method can be used for many applications, such as subwavelength imaging, detection, and electromagnetic monitoring, in both free space and complex environments.

Synthesis of the alkylated active metabolite of tipidogrel.

Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr-derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented.