Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

Corrosion at the cone/taper interface leads to failure of large-diameter metal-on-metal total hip arthroplasties.

BACKGROUND: Metal-on-metal (MoM) THAs have reduced wear rates compared with metal-on-polyethylene. However, elevated serum metal ion levels and pseudotumors have been reported in large MoM articulations. QUESTIONS/PURPOSES: We therefore determined (1) if corrosion occurred at the cone/taper interface leading to instability in patients with large-diameter THAs; (2) how patients presented clinically and radiographically; (3) if adverse periprosthetic tissue reactions occurred; (4) whether metal was released from the implants into the periprosthetic tissues; and (5) if head size correlated with metal release. METHODS: We reviewed 114 patients who had revisions of large-diameter head MoM articulations. Mean time of implantation was 46 months. To identify adverse reactions and particle load, tissues were stained by hematoxylin and eosin and CD3/CD20/CD68 antibodies. Periprosthetic tissues were analyzed for metal content and distribution in different regions. Electrochemical reactions between the stem and adapter were investigated by a minicell electrode. RESULTS: Electrochemical studies on the stem and the head adapter showed a risk for galvanic corrosion. Ninety-four percent of patients had instability at the cone/taper interface. All patients presented with early clinical symptoms; 59 patients had radiographic signs of loosening. One hundred four patients had foreign body reactions and necrosis. The largest amounts of metal released were titanium or iron. We found no correlation between head size and metal ion release. CONCLUSIONS: These findings suggest that in modular cone/taper connections, friction of the MoM articulations may cause failure of the cone/taper interface leading to galvanic corrosion and loosening. It is unclear whether the design of this MoM system provides sufficient stability at the taper.

Cytotoxic effects of the trifunctional bispecific antibody FBTA05 in ex-vivo cells of chronic lymphocytic leukaemia depend on immune-mediated mechanism.

Monoclonal antibodies such as rituximab and alemtuzumab show considerable therapeutic efficacy in chronic lymphocytic leukaemia (CLL). Aiming to further improve antineoplastic efficacy, the trifunctional bispecific antibody FBTA05 was developed. FBTA05 is thought to function by simultaneously binding B cells and T cells by its variable regions and by recruiting FcγR-positive accessory immune cells by its intact Fc region. As it was previously shown that this antibody shows considerable cytotoxicity towards a spectrum of B-cell lymphoma cell lines, we here tested its potential efficacy ex vivo against malignant B-CLL cells. Therefore, we assessed the capacity of increasing concentrations of FBTA05 to bind to neoplastic cells, to induce cytotoxicity (comparing it with rituximab and alemtuzumab) and cytokine release. We evaluated the results with respect to the extent of CD20 expression, the effector:target cell ratio as well as with the patients' overall effector cell status. Thus, we show that, although FBTA05-elicited cytotoxicity was comparable with that induced by alemtuzumab, it considerably exceeded the antineoplastic effects of rituximab. Noteworthy, FBTA05 shows effective elimination of malignant B cells even if CD20 surface expression is low. Importantly, a high grade of cytotoxicity was associated with the induction of T-cell proliferation and the concomittant release of interferon-γ and interleukin-6, thus overcoming the detrimental effects of an unfavourable effector:target cell ratio. In conclusion, we here present novel evidence for the therapeutic efficacy of the trifunctional, bispecific antibody FBTA05 in CLL and provide evidence for the importance of immune-mediated mechanisms conveying the cytotoxic effects against malignant B lymphocytes.

Prevalence of human metapneumovirus in central illinois in patients thought to have respiratory viral infection.

Studies suggest that by age 5 years nearly all people have been exposed to metapneumovirus. To determine its prevalence in central Illinois, we tested respiratory secretions by direct immunofluorescence staining from December to March. Metapneumovirus was detected in 11/391 specimens. The distribution of metapneumovirus was bimodal, with the split being between children aged

Breast cancer: a candidate gene approach across the estrogen metabolic pathway.

Polymorphisms within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated 11 genes encoding key proteins of this pathway for their potential contribution to breast cancer risk. Of these CYP17A1, CYP19A1, EPHX1, HSD17B1, SRD5A2, and PPARG2 participate in biosynthesis, CYP1A1, CYP1B1, COMT, GSTP1, and SOD2 in catabolism and detoxification. We performed a population-based case-control study with 688 incident breast cancer cases and 724 controls from Germany and genotyped 18 polymorphisms by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), PCR based RFLP (restriction fragment length polymorphism), and TaqMan allelic discrimination. Genotype frequencies were compared between cases and controls and odds ratios were calculated by conditional logistic regression. Further statistical analyses were based on cluster analysis, multifactor dimensionality reduction, logic regression, and global testing. Single factor analyses pointed to CYP1B1_1294_GG as a possible breast cancer risk modulator (OR = 2.57; 95% CI: 1.34-4.93) and two way stratification suggested associations between BMI > or = 30 kg/m(2) and COMT_472_GG (P = 0.0076 and P = 0.0026), BMI < 20 kg/m(2) and HSD17B1_937_GG (P = 0.0082) as well as CYP17A1_-34_CC and HRT use > or =10 years (P = 0.0063). Following correction for multiple testing none of these associations remained significant. No significant association between breast cancer risk and genetic polymorphisms was observed in multifactor analyses. The tested polymorphisms of the estrogen metabolic pathway may not play a direct role in breast cancer risk. Therefore, future association studies should be extended to other polymorphisms and other regulatory pathways.