A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: Synthesis and structure-activity relationships

a b s t r a c t A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior

Determination of Anthracene on Ag-Au Alloy Nanoparticles/Overoxidized-Polypyrrole Composite Modified Glassy Carbon Electrodes

A novel electrochemical sensor for the detection of anthracene was prepared by modifying a glassy carbon electrode (GCE) with over-oxidized polypyrrole (PPyox) and Ag-Au (1:3) bimetallic nanoparticles (Ag-AuNPs). The composite electrode (PPyox/Ag-AuNPs/GCE) was prepared by potentiodynamic polymerization of pyrrole on GCE followed by its overoxidation in 0.1 M NaOH. Ag-Au bimetallic nanoparticles were chemically prepared by the reduction of AgNO3 and HAuCl4 using C6H5O7Na3 as the reducing agent as well as the capping agent and then immobilized on the surface of the PPyox/GCE. The nanoparticles were characterized by UV-visible spectroscopy technique which confirmed the homogeneous formation of the bimetallic alloy nanoparticles. Transmission electron microscopy showed that the synthesized bimetallic nanoparticles were in the range of 20–50 nm. The electrochemical behaviour of anthracene at the PPyox/Ag-AuNPs/GCE with Ag: Au atomic ratio 25:75 (1:3) exhibited a higher electrocatalytic effect compared to that observed when GCE was modified with each constituent of the composite (i.e., PPyox, Ag-AuNPs) and bare GCE. A linear relationship between anodic current and anthracene concentration was attained over the range of 3.0 × 10−6 to 3.56 × 10−4 M with a detection limit of 1.69 × 10−7 M. The proposed method was simple, less time consuming and showed a high sensitivity

Department of Pathology, Thomas Jefferson University, Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors.

BACKGROUND: Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors. RESULTS: Unsupervised hierarchical clustering analysis showed that six models (TgWAP-Myc, TgMMTV-Neu, TgMMTV-PyMT, TgWAP-Int3, TgWAP-Tag, and TgC3(1)-Tag) yielded tumors with distinctive and homogeneous expression patterns within each strain. However, in each of four other models (TgWAP-T121, TgMMTV-Wnt1, Brca1Co/Co;TgMMTV-Cre;p53+/- and DMBA-induced), tumors with a variety of histologies and expression profiles developed. In many models, similarities to human breast tumors were recognized, including proliferation and human breast tumor subtype signatures. Significantly, tumors of several models displayed characteristics of human basal-like breast tumors, including two models with induced Brca1 deficiencies. Tumors of other murine models shared features and trended towards significance of gene enrichment with human luminal tumors; however, these murine tumors lacked expression of estrogen receptor (ER) and ER-regulated genes. TgMMTV-Neu tumors did not have a significant gene overlap with the human HER2+/ER- subtype and were more similar to human luminal tumors. CONCLUSION: Many of the defining characteristics of human subtypes were conserved among the mouse models. Although no single mouse model recapitulated all the expression features of a given human subtype, these shared expression features provide a common framework for an improved integration of murine mammary tumor models with human breast tumors

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors

Comparison of mammary tumor gene-expression profiles from thirteen murine models using microarrays and with that of human breast tumors showed that many of the defining characteristics of human subtypes were conserved among mouse models

Inflammation of the periodontium associates with risk of future cardiovascular events.

BackgroundWhile growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PDinflammation ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation.Methods18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PDinflammation and arterial inflammation were quantified using validated 18 F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PDinflammation and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests.ResultsThirteen individuals developed MACE during follow-up (median 4.1 years). PDinflammation associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized β [95% CI]: 0.30 [0.20-0.40], P < 0.001). PDinflammation predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PDinflammation and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022).ConclusionPDinflammation is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PDinflammation and CVD

Juveniles versus adults: differences in PGE2 levels in the gingival crevicular fluid during orthodontic tooth movement

This study aimed to investigate age-related changes in the biosynthetic capacity of prostaglandin E2 (PGE2) in the gingival crevicular fluid (GCF) during one month of orthodontic treatment. Twenty-five juvenile subjects (mean age 13 ± 2.1 years) and 23 adults (mean age 24 ± 2.1 years) were included. GCF was collected immediately before the force application at the baseline, 2, 21 and 28 days, with periopaper inserted into the gingival crevice of the maxillary lateral incisors. The mediator levels were determined with an EIA kit. The results showed that the PGE2 concentrations were significantly elevated from the baseline to 21 days (129.35 and 198.84 pg/µL, p = 0.0169) in juvenile subjects and reduced from 21 to 28 days (198.84 to 112.60 pg/µL, p = 0.0032). Adults, however, had no significant changes in the PGE2 levels. The total amounts of PGE2 from both groups changed between the baseline to 21 and 21 to 28 days (p = 0.0119 and p = 0.0076, respectively). The PGE2 initial and final levels showed significant differences between the juveniles and adults, being higher in adults (baseline: juvenile = 129.35 pg/µL vs. adult = 163.20 pg/µL, p = 0.0379; t3: juvenile = 112.60 pg/µL and adult = 175.30 pg/µL, p = 0.0005). In conclusion, the results demonstrate the presence of variation in the PGE2 levels according to age and the orthodontic activation period, which can explain why the speed of orthodontics treatment may be different in adults vs. juveniles

Unsupervised cluster analysis of the combined gene expression data for 232 human breast tumor samples and 122 mouse mammary tumor samples

<p><b>Copyright information:</b></p><p>Taken from "Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors"</p><p>http://genomebiology.com/2007/8/5/R76</p><p>Genome Biology 2007;8(5):R76-R76.</p><p>Published online 10 May 2007</p><p>PMCID:PMC1929138.</p><p></p> A color-coded matrix below the dendrogram identifies each sample; the first two rows show clinical ER and HER2 status, respectively, with red = positive, green = negative, and gray = not tested; the third row includes all human samples colored by intrinsic subtype as determined from Additional data file 6; red = basal-like, blue = luminal, pink = HER2+/ER-, yellow = claudin-low and green = normal breast-like. The remaining rows correspond to murine models indicated at the right. A gene cluster containing basal epithelial genes. A luminal epithelial gene cluster that includes and . A second luminal cluster containing 8 and 18. Proliferation gene cluster. Interferon-regulated genes. Fibroblast/mesenchymal enriched gene cluster. The amplicon cluster. See Additional data file 5 for the complete cluster diagram