Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells

Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic options. Highly substituted ansatitanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives of this study are to examine the effects of these titanocene compounds on prostate cancer cells. Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin. Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal microscopy. These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent apoptosis following treatment with all the titanocene compounds. This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer.

Comments on 'Balance and the slow quasimanifold: some explicit results'

The concept of slow vortical dynamics and its role in theoretical understanding is central to geophysical fluid dynamics. It leads, for example, to ���potential vorticity thinking��� (Hoskins et al. 1985). Mathematically, one imagines an invariant manifold within the phase space of solutions, called the slow manifold (Leith 1980; Lorenz 1980), to which the dynamics are constrained. Whether this slow manifold truly exists has been a major subject of inquiry over the past 20 years. It has become clear that an exact slow manifold is an exceptional case, restricted to steady or perhaps temporally periodic flows (Warn 1997). Thus the concept of a ���fuzzy slow manifold��� (Warn and M��nard 1986) has been suggested. The idea is that nearly slow dynamics will occur in a stochastic layer about the putative slow manifold. The natural question then is, how thick is this layer? In a recent paper, Ford et al. (2000) argue that Lighthill emission���the spontaneous emission of freely propagating acoustic waves by unsteady vortical flows���is applicable to the problem of balance, with the Mach number Ma replaced by the Froude number F, and that it is a fundamental mechanism for this fuzziness. They consider the rotating shallow-water equations and find emission of inertia���gravity waves at O(F2). This is rather surprising at first sight, because several studies of balanced dynamics with the rotating shallow-water equations have gone beyond second order in F, and found only an exponentially small unbalanced component (Warn and M��nard 1986; Lorenz and Krishnamurthy 1987; Bokhove and Shepherd 1996; Wirosoetisno and Shepherd 2000). We have no technical objection to the analysis of Ford et al. (2000), but wish to point out that it depends crucially on R 1, where R is the Rossby number. This condition requires the ratio of the characteristic length scale of the flow L to the Rossby deformation radius LR to go to zero in the limit F ��� 0. This is the low Froude number scaling of Charney (1963), which, while originally designed for the Tropics, has been argued to be also relevant to mesoscale dynamics (Riley et al. 1981). If L/LR is fixed, however, then F ��� 0 implies R ��� 0, which is the standard quasigeostrophic scaling of Charney (1948; see, e.g., Pedlosky 1987). In this limit there is reason to expect the fuzziness of the slow manifold to be ���exponentially thin,��� and balance to be much more accurate than is consistent with (algebraic) Lighthill emission.

The Aedes aegypti larval transcriptome: a comparative perspective with emphasis on trypsins and the domain structure of peritrophins

The genome sequence of Aedes aegypti was recently reported. A significant amount of Expressed Sequence Tags (ESTs) were sequenced to aid in the gene prediction process. In the present work we describe an integrated analysis of the genomic and EST data, focusing on genes with preferential expression in larvae (LG), adults (AG) and in both stages (SG). A total of 913 genes (5.4% of the transcript complement) are LG, including ion transporters and cuticle proteins that are important for ion homeostasis and defense. From a starting set of 245 genes encoding the trypsin domain, we identified 66 putative LG, AG, and SG trypsins by manual curation. Phylogenetic analyses showed that AG trypsins are divergent from their larval counterparts (LG), grouping with blood-induced trypsins from Anopheles gambiae and Simulium vittatum. These results support the hypothesis that blood-feeding arose only once, in the ancestral Culicomorpha. Peritrophins are proteins that interlock chitin fibrils to form the peritrophic membrane (PM) that compartmentalizes the food in the midgut. These proteins are recognized by having chitin-binding domains with 6 conserved Cys and may also present mucin-like domains (regions expected to be highly O-glycosylated). PM may be formed by a ring of cells (type 2, seen in Ae. aegypti larvae and Drosophila melanogaster) or by most midgut cells (type 1, found in Ae. aegypti adult and Tribolium castaneum). LG and D. melanogaster peritrophins have more complex domain structures than AG and T. castaneum peritrophins. Furthermore, mucin-like domains of peritrophins from T. castaneum (feeding on rough food) are lengthier than those of adult Ae. aegypti (blood-feeding). This suggests, for the first time, that type 1 and type 2 PM may have variable molecular architectures determined by different peritrophins and/or ancillary proteins, which may be partly modulated by diet.

Effect of intraperitoneal or incisional bupivacaine on pain and the analgesic requirement after ovariohysterectomy in dogs

Objective To compare the effect of intraperitoneal (IP) or incisional (INC) bupivacaine on pain and the analgesic requirement after ovariohysterectomy in dogs.Study design Prospective, randomized clinical study.Animals Thirty female dogs undergoing ovariohysterectomy (OHE).Methods Dogs admitted for elective OHE were anesthetized with acepromazine, butorphanol, thiopental and halothane. Animals were randomly assigned to one of three groups (n = 10 per group). The treatments consisted of preincisional infiltration with saline solution (NaCl 0.9%) or bupivacaine with epinephrine and/or IP administration of the same solutions, as follows: INC and IP 0.9% NaCl (control group); INC 0.9% NaCl and IP bupivacaine (5 mg kg(-1), IP group); INC bupivacaine (1 mg kg(-1)) and IP 0.9% NaCl (INC group). Postoperative pain was evaluated by a blinded observer for 24 hours after extubation by means of a visual analog scale (VAS) and a numeric rating scale (NRS). Rescue analgesia (morphine, 0.5 mg kg(-1), IM) was administered if the VAS was > 5/10 or the NRS > 10/29.Results At 1 hour after anesthesia, VAS pain scores were [medians (interquartile range)]: 6.4 (3.1-7.9), 0.3 (0.0-2.6) and 0.0 (0.0-7.0) in control, IP and INC groups, respectively. VAS pain scores were lower in the IP compared to the control group. Over the first 24 hours, rescue analgesia was administered to 7/10, 5/10 and 3/10 dogs of the control, INC and IP groups, respectively. Total number of dogs given rescue analgesia over the first 24 hours did not differ significantly among groups.Conclusions and clinical relevance Intraperitoneal bupivacaine resulted in lower pain scores during the first hour of the postoperative period and there was a trend towards a decreased need for rescue analgesia after OHE in dogs.

Report of Colloquium on Statistics and the New Technologies

Includes bibliography