Low energy X-ray dosimeter based on LYSO:Ce fluorescent powder.

Cerium-doped lutetium yttrium orthosilicate (LYSO:Ce) powder has been synthesized by the co-precipitation method. The influence of the Ce3+ doping concentration on the lattice structure and luminescence characteristics of LYSO:Ce powder was investigated by X-ray diffraction (XRD) and photoluminescence (PL). The XRD measurement indicates that the lattice structure of LYSO:Ce powder was not changed by doping ions. PL results show that LYSO:Ce powder has better luminescence performance when the Ce doping concentration is 0.3 mol%. In addition, the fluorescence lifetime of the samples was measured, and the results show that LYSO:Ce has a short decay time. The radiation dosimeter was prepared by LYSO:Ce powder with a Ce doping concentration of 0.3 mol%. Radioluminescence properties of the radiation dosimeter also were studied under X-ray irradiation at doses from 0.03 to 0.76 Gy, with dose rate from 0.09 to 2.284 Gy/min. The results show that the dosimeter has a certain linear relationship response and stability. The radiation responses of the dosimeter at different energies were obtained under X-ray irradiation with X-ray tube voltages ranging from 20 to 80 kV. The results show that the dosimeter has a certain linear relationship response in the low energy range of radiotherapy. These results indicate the potential application of LYSO:Ce powder dosimeters in remote radiotherapy and online radiation monitoring.

Extended state observer-based fixed-time trajectory tracking control of autonomous surface vessels with uncertainties and output constraints.

A fixed-time trajectory tracking control of autonomous surface vessels (ASVs) subject to unmeasured speed is studied in this work. By using the homogeneity-based Lyapunov method, the unknown system states, including the unmeasured speed and lumped disturbances, are estimated by using a novel extended state observer (ESO) within fixed time. Subsequently, using the estimated states, the task of fixed-time tracking is completed with the aid of a newly proposed output-constrained power integrator method, which makes the vessel position and heading strictly within the predefined output constraints, and the tracking errors can be reduced to a range of zero under the continuous control action. The practical fixed-time stability (FTS) of the closed-loop system is analyzed in the sense of Lyapunov, while the output constraints can be well maintained during maneuvering. Finally, the ascendancy of the designed scheme is exhibited by simulation comparisons.

Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers.

Interactions between cancer cells and their microenvironment are critical for the development and progression of solid tumors. This study is the first to examine the role of all members of the ErbB tyrosine kinase receptors (epidermal growth factor receptor [EGFR], ErbB-2, ErbB-3, or ErbB-4), expressed singly or as paired receptor combinations, in the regulation of angiogenesis both in vitro and in vivo. Comparison of all receptor combinations reveals that EGFR/ErbB-2 and ErbB-2/ErbB-3 heterodimers are the most potent inducers of vascular endothelial growth factor (VEGF) mRNA expression compared with EGFR/ErbB-3, EGFR/ErbB-4, ErbB-2/ErbB-4, and ErbB-3/ErbB-4. Immunohistochemistry of tumor xenografts overexpressing these heterodimers shows increased VEGF expression and remarkably enhanced vascularity. Enhanced VEGF expression is associated with increased VEGF transcription. Deletional analysis reveals that ErbB-mediated transcriptional up-regulation of VEGF involves a hypoxia-inducible factor 1-independent responsive region located between nucleotides -88 to -66 of the VEGF promoter. Mutational analysis reveals that the Sp-1 and AP-2 transcription factor binding elements within this region are required for up-regulation of VEGF by heregulin beta1 and that this up-regulation is dependent on the activity of extracellular signal-related protein kinases. These results emphasize the biological implications of cell signaling diversity among members of the ErbB receptor family in regulation of the tumor microenvironment.

Regulation of multiple tumor microenvironment markers by overexpression of single or paired combinations of ErbB receptors.

The progression of primary tumors to an invasive phenotype requires dynamic changes in multiple cellular and local tumor microenvironment markers. In this study, we report a genomic approach to assess gene transcriptional changes upon overexpression of ErbB receptors, in vitro and in vivo, focusing on markers involved in the regulation of the tumor microenvironment. ErbB receptors (ErbB-1/epidermal growth factor receptor, ErbB-2, ErbB-3, and ErbB-4) were stably overexpressed in a polyclonal cell population as single or paired combinations using murine and human breast cell models. The overall numbers of known genes that are up- or down-regulated was significantly higher in cells and tumors overexpressing paired combinations of receptors compared with cells and tumors overexpressing single ErbB receptors. Genes encoding components of cell-cell structures, extracellular matrix, coagulation factors, and angiogenesis were predominantly affected by the most active ErbB receptor combinations and were predictive of the aggressive in vivo tumorigenicity, a feature that was not always seen in vitro. Among ErbB-regulated tumor microenvironment markers detected by the genomic analysis, thrombospondin 1, an endogenous inhibitor of angiogenesis, was additionally validated in relation to tumor growth phenotype. Thrombospondin 1 mRNA and protein were down-regulated by specific ErbB receptors, in vitro and in both rodent and human ErbB-induced tumors, consistent with the extent of tumor growth and tumor vascularization associated with specific ErbB receptors. In summary, our genomic results highlight the broad diversity of ErbB-regulated cancer-associated genes and revealed several novel targets that may have potential therapeutic applications for targeting tumor progression involving aberrations of ErbB receptors.

Cdc25A-inhibitory properties and antineoplastic activity of bisperoxovanadium analogues.

Bisperoxovanadium (bpV) compounds are irreversible protein tyrosine phosphatase (PTP) inhibitors with a spectrum of activity distinct from that of vanadium salts. We studied the efficacy of a panel of bpVs as antineoplastic agents in vitro and in vivo with a view to investigating phosphatases as potential antineoplastic targets. The Cdc25A dual-specificity phosphatase is an oncoprotein required for progression through G(1)-S. It cooperates with oncogenic Ras to transform cells and is overexpressed in several cancers. Cdc25A is therefore an attractive candidate phosphatase target for the antineoplastic activity of bpV compounds. Cytotoxicity was examined in 28 cancer cell lines and in vivo efficacy was examined in a DA3 murine mammary carcinoma model. In vitro phosphatase assays were used to directly measure phosphatase inhibition, comparing Cdc25A to hVH2/DSP4, leukocyte antigen related/receptor type PTPF catalytic domain (LAR), Yersinia pestis phosphatase (YOPH), and T-cell PTPase/non-receptor type PTP2 (TCPTP). CDK2 activity and Rb phosphorylation were examined by immunocomplex kinase assays and Western blot. Cdc25A is at least 20-fold more sensitive to bpV inhibition than hVH2/DSP4, and 3- to 10- fold more sensitive than TCPTP and LAR. bpV inhibition of Cdc25A in cells leads to CDK2 inactivation and hypophosphorylation Rb, resulting in G1-S arrest and induction of p53-independent apoptosis. The most cytotoxic analogue, bpV[4,7-dimethyl-1,10-phenanthroline-bisperoxo-oxo-vanadium (Me2Phen)], shows submicromolar IC50s against a panel of cell lines and inhibited tumor growth by 80% in mice. These results demonstrate that bpVs may have significant antineoplastic activity. In addition, they are in vitro and in vivo inhibitors of phosphatases including Cdc25A, suggesting that phosphatases may be appropriate targets for novel antineoplastic agents and that further development of these agents, targeting them to specific phosphatases such as CDC25A, may lead to novel agents with enhanced antineoplastic activity.

Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue.

A novel naturally occurring antiangiogenic agent isolated from cartilage, referred to as Neovastat (AE-941), was examined for its efficacy against tumor neovascularization and progression. Exposure to Neovastat results in ex ovo antiangiogenic properties in the chorioallantoid membrane of chicken embryo (71% decrease in the angiogenic index as compared to the basic fibroblast growth factor (bFGF) treated control embryos, P < 0.0001). Oral administration of Neovastat inhibits bFGF-induced angiogenesis in the Matrigel mouse model (87.5% decrease in hemoglobin as compared to the bFGF-treated control implants, P < 0.0001). Neovastat also induces a dose response decrease of lung metastases in the Lewis lung carcinoma model (oral administration; 69.1% of inhibition obtained at the maximal dose of 0.5 ml/day, P < 0.0001). Combined with a sub-optimal dose of cisplatinum (2 mg/kg, i.p.), Neovastat (0.5 ml/day) improved the therapeutic index by increasing the antimetastatic efficacy and by exerting a protective activity against cisplatinum-induced body weight loss and myelosuppression. In summary, our experimental data provide evidence of antiangiogenic and antimetastatic properties of Neovastat, following oral administration.

Retroviral delivery of connexin genes to human breast tumor cells inhibits in vivo tumor growth by a mechanism that is independent of significant gap junctional intercellular communication.

The mechanism by which gap junction proteins, connexins, act as potent tumor suppressors remains poorly understood. In this study human breast tumor cells were found to exhibit diverse gap junction phenotypes including (a) undetectable Cx43 and no intercellular communication (HBL100); (b) low levels of Cx43 and sparse intercellular communication (MDA-MB-231); and (c) significant levels of Cx43 and moderate intercellular communication (Hs578T). Although retroviral delivery of Cx43 and Cx26 cDNAs to MDA-MB-231 cells did not achieve an expected substantial rescue of intercellular communication, overexpression of connexin genes did result in a dramatic suppression of tumor growth when connexin-expressing MDA-MB-231 cells were implanted into the mammary fat pad of nude mice. Subsequent immunolocalization studies on xenograph sections revealed only cytoplasmic stores of Cx43 and no detectable gap junctions. Moreover, DNA array and Western blot analysis demonstrated that overexpression of Cx43 or Cx26 in MDA-MB-231 cells down-regulated fibroblast growth factor receptor-3. Surprisingly, these results suggest that Cx43 and Cx26 induce their tumor-suppressing properties by a mechanism that is independent of significant gap junctional intercellular communication and possibly through the down-regulation of key genes involved in tumor growth. Moreover, our studies show that retroviruses are effective vehicles for delivering connexins to human breast tumor cells, facilitating potential gene therapy applications.