Molecular lens applied to benzene and carbon disulfide molecular beams

A molecular lens of the nonresonant dipole force formed by focusing a nanosecond IR laser pulse has been applied to benzene and CS2 molecular beams. Using the velocity map imaging technique for molecular ray tracing, characteristic molecular lens parameters including the focal length (f ), minimum beam width (W), and distance to the minimum beam width position (D) were determined. The laser intensity dependence of the observed lens parameters was in good agreement with theoretical predictions. W was independent of the laser peak intensity (I-0), whereas f and D varied linearly with 1/I-0. The differences in lens parameters between the molecular species were well correlated with the polarizability per mass values of the molecules. A high chromatographic resolution of Rs = 0.84 was achieved between the images of benzene molecular beams undeflected and deflected by the lens. The possibilities for a new type of chromatography are discussed.open293

Rapid translocation of nanoparticles from the lung airspaces to the body

Nano-size particles show promise for pulmonary drug delivery, yet their behavior after deposition in the lung remains poorly understood. In this study, a series of near-infrared (NIR) fluorescent nanoparticles were systematically varied in chemical composition, shape, size and surface charge, and their biodistribution and elimination were quantified in rat models after lung instillation. We demonstrate that nanoparticles with hydrodynamic diameter (HD) less than ≈34 nm and a noncationic surface charge translocate rapidly from the lung to mediastinal lymph nodes. Nanoparticles of HD < 6 nm can traffic rapidly from the lungs to lymph nodes and the bloodstream, and then be subsequently cleared by the kidneys. We discuss the importance of these findings for drug delivery, air pollution and carcinogenesis

Transgenic tomatoes expressing human beta-amyloid for use as a vaccine against Alzheimer’s disease

Human β-amyloid (Aβ) is believed to be one of the main components of Alzheimer’s disease, so reduction of Aβ is considered a key therapeutic target. Using Agrobacterium-mediated nuclear transformation, we generated transgenic tomatoes for Aβ with tandem repeats. Integration of the human Aβ gene into the tomato genome and its transcription were detected by PCR and Northern blot, respectively. Expression of the Aβ protein was confirmed by western blot and ELISA, and then the transgenic tomato line expressing the highest protein level was selected for vaccination. Mice immunized orally with total soluble extracts from the transgenic tomato plants elicited an immune response after receiving a booster. The results indicate that tomato plants may provide a useful system for the production of human Aβ antigen

Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers

Objective Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole. Methods In this randomized, single-blind, two-way crossover study, 32 healthy volunteers received placebo, followed by a single 5-mg oral dose of axitinib, administered either alone or on the fourth day of dosing with oral ketoconazole (400 mg/day for 7 days). Results Axitinib exposure was significantly increased in the presence of ketoconazole, with a geometric mean ratio for area under the plasma concentration–time curve from time zero to infinity of 2.06 (90% confidence interval [CI]: 1.84–2.30) and a geometric mean ratio for maximum plasma concentration (Cmax) of 1.50 (90% CI: 1.33–1.70). For axitinib alone or with ketoconazole, Cmax occurred 1.5 and 2.0 h after dosing, respectively. Adverse events were predominantly mild; the most commonly reported treatment-related adverse events were headache and nausea. Conclusions Axitinib plasma exposures and peak concentrations were increased following concurrent administration of axitinib and ketoconazole in healthy volunteers. Axitinib alone and in combination with ketoconazole was well tolerated. These findings provide an upper exposure for expected axitinib plasma concentrations in the presence of potent metabolic inhibition

En bloc Extended Total Thymectomy and Extrapleural Pneumonectomy in Masaoka stage IVA Thymomas

<p>Abstract</p> <p>Background</p> <p>Surgical excision is the primary treatment for a thymoma. However, for advanced thymoma that extends to within the thoracic cavity and for recurrent cases with pleural dissemination (Masaoka stage IVA), the appropriate treatment is controversial. We evaluated the safety of surgery and outcomes of seven patients that underwent an en bloc extended total thymectomy and extrapleural pneumonectomy for stage IVA thymomas.</p> <p>Methods</p> <p>From 1994 to 2009, five patients initially diagnosed with pleural dissemination and two patients with recurrent tumors in the pleura and lungs after a total thymectomy, were identified. Seven patients had an extrapleural pneumonectomy performed. For the first operation, five patients underwent additional en bloc extended total thymectomy.</p> <p>Results</p> <p>Two recurrent cases were identified 55.2 and 12.3 months after first operation. Two patients had WHO type B1-B2 tumors, two had B2, two had B2-B3, and one had a B3 tumor. The mean hospital stay was 15.3 days (range: 7-29). There was no operative mortality. Four patients had neoadjuvant chemotherapy and five were treated with adjuvant chemotherapy. The median survival was 30.6 months and the Kaplan-Meier 2-year survival was 100% (95% confidence interval: 24.6-36.6 months). One patient, who did not receive induction chemotherapy, had distant metastases after surgery.</p> <p>Conclusions</p> <p>En bloc extended total thymectomy and extrapleural pneumonectomy can be safely performed on selected patients with stage IVA thymomas and is expected to achieve complete local control. Although the treatment strategy has yet to be standardized, complete resection with appropriate systemic therapy may improve survival in otherwise fatal disease.</p

Constitutive activation of glycogen synthase kinase-3β correlates with better prognosis and cyclin-dependent kinase inhibitors in human gastric cancer

Background: Aberrant regulation of glycogen synthase kinase-3 beta (GSK-3 beta) has been implicated in several human cancers; however, it has not been reported in the gastric cancer tissues to date. The present study was performed to determine the expression status of active form of GSK-3 beta phosphorylated at Tyr(216) (pGSK-3 beta) and its relationship with other tumor-associated proteins in human gastric cancers. Methods: Immunohistochemistry was performed on tissue array slides containing 281 human gastric carcinoma specimens. In addition, gastric cancer cells were cultured and treated with a GSK-3 beta inhibitor lithium chloride (LiCl) for immunoblot analysis. Results: We found that pGSK-3 beta was expressed in 129 (46%) of 281 cases examined, and was higher in the early-stages of pathologic tumor-node-metastasis (P < 0.001). The expression of pGSK-3 beta inversely correlated with lymphatic invasion (P < 0.001) and lymph node metastasis (P < 0.001) and correlated with a longer patient survival (P < 0.001). In addition, pGSK-3 beta expression positively correlated with that of p16, p21, p27, p53, APC, PTEN, MGMT, SMAD4, or KAl1 (P < 0.05), but not with that of cyclin D1. This was confirmed by immunoblot analysis using SNU-668 gastric cancer cells treated with LiCl. Conclusions: GSK-3 beta activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis. Thus, these findings suggest that GSK-3 beta activation is a useful prognostic marker for the early-stage gastric cancer.Hirakawa H, 2009, ONCOL REP, V22, P481, DOI 10.3892/or_00000460Dar AA, 2009, ONCOGENE, V28, P866, DOI 10.1038/onc.2008.434Holmes T, 2008, STEM CELLS, V26, P1288, DOI 10.1634/stemcells.2007-0600Wang Q, 2008, CELL DEATH DIFFER, V15, P908, DOI 10.1038/cdd.2008.2Takahashi-Yanaga F, 2008, CELL SIGNAL, V20, P581, DOI 10.1016/j.cellsig.2007.10.018Pan MH, 2007, J AGR FOOD CHEM, V55, P7777, DOI 10.1021/jf071520hShakoori A, 2007, CANCER SCI, V98, P1388, DOI 10.1111/j.1349-7006.2007.00545.xZheng HC, 2007, ANTICANCER RES, V27, P3561Saegusa M, 2007, J PATHOL, V213, P35, DOI 10.1002/path.2198Ma C, 2007, CANCER RES, V67, P7756, DOI 10.1158/0008-5472.CAN-06-4665Forde JE, 2007, CELL MOL LIFE SCI, V64, P1930, DOI 10.1007/s00018-007-7045-7Li YW, 2007, J BIOL CHEM, V282, P21542, DOI 10.1074/jbc.M701978200Ding QQ, 2007, CANCER RES, V67, P4564, DOI 10.1158/0008-5472.CAN-06-1788Kunnimalaiyaan M, 2007, MOL CANCER THER, V6, P1151, DOI 10.1158/1535-7163.MCT-06-0665Soto-Cerrato V, 2007, MOL CANCER THER, V6, P362, DOI 10.1158/1535-7163.MCT-06-0266Cao Q, 2006, CELL RES, V16, P671, DOI 10.1038/sj.cr.7310078Yang CH, 2006, PRECIS AGRIC, V7, P33, DOI 10.1007/s11119-005-6788-0Crew KD, 2006, WORLD J GASTROENTERO, V12, P354Mai W, 2007, ONCOLOGY-BASEL, V71, P297, DOI 10.1159/000106429Tan J, 2005, CANCER RES, V65, P9012, DOI 10.1158/0008-5472.CAN-05-1226Shakoori A, 2005, BIOCHEM BIOPH RES CO, V334, P1365, DOI 10.1016/j.bbrc.2005.07.041Farago M, 2005, CANCER RES, V65, P5792Ghosh JC, 2005, CLIN CANCER RES, V11, P4580Liao XB, 2003, MOL CANCER THER, V2, P1215Lee HS, 2003, J PATHOL, V200, P39, DOI 10.1002/path.1288Doble BW, 2003, J CELL SCI, V116, P1175, DOI 10.1242/jcs.00384Gotoh J, 2003, CARCINOGENESIS, V24, P435Goto H, 2002, ORAL ONCOL, V38, P549Lee HS, 2001, INT J CANCER, V91, P619D`Amico M, 2000, J BIOL CHEM, V275, P32649, DOI 10.1074/jbc.M000643200Endoh Y, 2000, J PATHOL, V191, P257Wu LY, 1998, J NATL MED ASSOC, V90, P410WOODGETT JR, 1984, BIOCHIM BIOPHYS ACTA, V788, P339