Aurora-A/STK15/BTAK overexpression induces centrosome amplification, chromosomal instability, and transformation in human urothelial cells

Aurora-A/STK15/BTAK kinase encoding gene, located on chromosome 20q13, is frequently amplified and overexpressed in human cancers. Sen et al. previously demonstrated that Aurora-A amplification and overexpression are associated with aneuploidy and clinically aggressive bladder cancer (J Natl Cancer Inst (2002) 94, 1320-1329). To examine if this association is the direct result of Aurora-A gene amplification and overexpression, an immortalized human urothelial cell line (SV-HUC) was infected with an adenoviral Aurora-A-green fluorescent protein (Ad-Aurora-A-GFP) fusion construct inducing ectopic expression of the resulting fusion protein. Controls included mock-infected and adenoviral-GFP infected cells. Ectopic expression of transduced Aurora-A did not alter the doubling time of the SV-HUC cells but significantly increased the number of cells with multiple centrosomes displaying aneuploidy and increased colony formation in soft agar. This is the first report demonstrating that overexpression of Aurora-A induces centrosome anomalies together with chromosomal instability and malignant transformation-associated phenotypic changes in immortalized human urothelial cells, thus supporting the hypothesis that this gene plays an important role in the development of aggressive bladder cancer

Controversies in the management of advanced prostate cancer

For advanced prostate cancer, the main hormone treatment against which other treatments are assessed is surgical castration. It is simple, safe and effective, however it is not acceptable to all patients. Medical castration by means of luteinizing hormone-releasing hormone (LH-RH) analogues such as goserelin acetate provides an alternative to surgical castration. Diethylstilboestrol, previously the only non-surgical alternative to orchidectomy, is no longer routinely used. Castration reduces serum testosterone by around 90%, but does not affect androgen biosynthesis in the adrenal glands. Addition of an anti-androgen to medical or surgical castration blocks the effect of remaining testosterone on prostate cells and is termed combined androgen blockade (CAB). CAB has now been compared with castration alone (medical and surgical) in numerous clinical trials. Some trials show advantage of CAB over castration, whereas others report no significant difference. The author favours the view that CAB has an advantage over castration. No study has reported that CAB is less effective than castration. Of the anti-androgens which are available for use in CAB, bicalutamide may be associated with a lower incidence of side-effects compared with the other non-steroidal anti-androgens and, in common with nilutamide, has the advantage of once-daily dosing. Only one study has compared anti-androgens within CAB: bicalutamide plus LH-RH analogue and flutamide plus LH-RH analogue. At 160-week follow-up, the groups were equivalent in terms of survival and time to progression. However, bicalutamide caused significantly less diarrhoea than flutamide. Withdrawal and intermittent therapy with anti-androgens extend the range of treatment options. © 1999 Cancer Research Campaig

Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models

Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols

Intravesical chemotherapy and immunotherapy for superficial tumors: basic mechanism of action and future direction

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Hole Transport in Low-Donor-Content Organic Solar Cells

Organic solar cells with an electron donor diluted in a fullerene matrix have a reduced density of donor-fullerene contacts, resulting in decreased free-carrier recombination and increased open-circuit voltages. However, the low donor concentration prevents the formation of percolation pathways for holes. Notwithstanding, high (>75%) external quantum efficiencies can be reached, suggesting an effective holetransport mechanism. Here, we perform a systematic study of the hole mobilities of 18 donors, diluted at ∼6 mol % in C60, with varying frontier energy level offsets and relaxation energies. We find that hole transport between isolated donor molecules occurs by long-range tunneling through several fullerene molecules, with the hole mobilities being correlated to the relaxation energy of the donor. The transport mechanism presented in this study is of general relevance to bulk heterojunction organic solar cells where mixed phases of fullerene containing a small fraction of a donor material or vice versa are present as well

Hole transport in low-donor-content organic solar cells

Organic solar cells with an electron donor diluted in a fullerene matrix have a reduced density of donor-fullerene contacts, resulting in decreased free-carrier recombination and increased open-circuit voltages. However, the low donor concentration prevents the formation of percolation pathways for holes. Notwithstanding, high (>75%) external quantum efficiencies can be reached, suggesting an effective hole-transport mechanism. Here, we perform a systematic study of the hole mobilities of 18 donors, diluted at ∼6 mol % in C60, with varying frontier energy level offsets and relaxation energies. We find that hole transport between isolated donor molecules occurs by long-range tunneling through several fullerene molecules, with the hole mobilities being correlated to the relaxation energy of the donor. The transport mechanism presented in this study is of general relevance to bulk heterojunction organic solar cells where mixed phases of fullerene containing a small fraction of a donor material or vice versa are present as well

Hole transport in low-donor-content organic solar cells

Organic solar cells with an electron donor diluted in a fullerene matrix have a reduced density of donor-fullerene contacts, resulting in decreased free-carrier recombination and increased open-circuit voltages. However, the low donor concentration prevents the formation of percolation pathways for holes. Notwithstanding, high (>75%) external quantum efficiencies can be reached, suggesting an effective hole-transport mechanism. Here, we perform a systematic study of the hole mobilities of 18 donors, diluted at ∼6 mol % in C60, with varying frontier energy level offsets and relaxation energies. We find that hole transport between isolated donor molecules occurs by long-range tunneling through several fullerene molecules, with the hole mobilities being correlated to the relaxation energy of the donor. The transport mechanism presented in this study is of general relevance to bulk heterojunction organic solar cells where mixed phases of fullerene containing a small fraction of a donor material or vice versa are present as well

Manipulating the Charge Transfer Absorption for Narrowband Light Detection in the Near-Infrared

Charge generation and recombination pro- cesses at interfaces between electron donating (donor, D) and accepting molecules (acceptor, A) are mediated by intermolecular charge-transfer (CT) states. Since organic photovoltaic and photodetecting devices rely on D−A interfaces, an understanding of the molecular and morpho- logical aspects governing CT state properties is crucial. In this paper, we synthesize a novel series of bi(thio)pyranylidene donor molecules and show how the interplay of molecular structure and energy levels in a D−C60 blend affect the line shape of the CT absorption cross section. By rationally designing the molecule 2,2′,6,6′-tetra-(2-methylthienyl)-4,4′- bithiopyranylidene, we achieve a 2 times stronger CT absorption peak than the literature-known molecule 2,2′,6,6′-tetraphenyl-4,4′-bipyranylidene when blended with C60. The low CT state energy combined with relatively strong CT absorption of this new material blend is exploited by fabricating near- infrared, cavity enhanced narrowband detectors. The photodetectors cover an impressive wavelength range from 810 to 1665 nm with line widths between 30 and 50 nm

Molecular parameters responsible for thermally activated transport in doped organic semiconductors

Doped organic semiconductors typically exhibit a thermal activation of their electrical conductivity, whose physical origin is still under scientific debate. In this study, we disclose relationships between molecular parameters and the thermal activation energy (EA) of the conductivity, revealing that charge transport is controlled by the properties of host–dopant integer charge transfer complexes (ICTCs) in efficiently doped organic semiconductors. At low doping concentrations, charge transport is limited by the Coulomb binding energy of ICTCs, which can be minimized by systematic modification of the charge distribution on the individual ions. The investigation of a wide variety of material systems reveals that static energetic disorder induced by ICTC dipole moments sets a general lower limit for EA at large doping concentrations. The impact of disorder can be reduced by adjusting the ICTC density and the intramolecular relaxation energy of host ions, allowing an increase of conductivity by many orders of magnitude