Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells

Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6-14 μM), zoledronic acid (IC50 = 21-57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer

"The cuts they trimmed the people" School children, precarity and citizenship

Recently, the Education, Audiovisual and Culture Executive Agency (2012) have funded programmes designed to advance European citizenship and citizen competences through education. This paper reports on the findings from one project, Creative Connections, designed to encourage the “voices” of young people in exploring European identities. Children (aged 9–16) in 25 schools in six European Union (EU) countries (UK, Finland, Spain, Czech Republic, Portugal and Ireland) developed artworks that explored perceptions of European citizenship. Their art was posted on a secure website and they discussed images with peers using automatic online translated blogs. The project facilitated representations of identity/belonging using a range of media. However, some artworks suggested that children were alienated from “Europe”, particularly EU responses to global austerity. This paper uses the theory of precarity to examine the ways in which the children expressed their concerns. Some artworks suggest that recent economic and political decisions have had the effect of challenging a sense of shared European citizenship; they resist a positive sense of identification with Europe and demonstrate fear for their future based on their current lives. This indicates that the EU’s educational goals to promote citizenship competences may require revision to account for the challenges of contemporary societies

Estimation of Actuation System Parameters for Lower Limb Prostheses

This paper provides guidelines to estimate the kinematics, energy and torque requirements for lower limb prosthetic actuation systems during daily living activities. These parameters are estimated based on human biomechanical data from different sources to consider the variability due to the assumptions and errors in the analysis and data collection. The results showed that the powered actuation source is important at the ankle joint in the stance phase during level ground walking while it is more important at knee joint during stair ascending. These estimated parameters can be used as guidelines to design and select proper actuation systems

Investigation into Energy Efficiency and Regeneration in an Electric Prosthetic Knee

Powered lower limb prosthesis are facing energy and efficiency challenges. This article presents an investigation into reducing the energy losses and increasing the efficiencies of energy regeneration for a powered prosthetic knee during level ground walking. The results showed that the regeneration and overall system efficiencies would dramatically increase if the negative mechanical load in the braking quadrants are within the regenerative zone of the motor. This approach reduced the energy losses in the stance and swing phases and increased the possibility of harvesting more negative mechanical energy during level ground walking

Isochondodendrine and 2[prime or minute]-norcocsuline: additional alkaloids from Triclisia subcordata induce cytotoxicity and apoptosis in ovarian cancer cell lines

Triclisia subcordata Oliv (Menispermeaceae) is used in herbal medicine for the treatment of cancer and other diseases in Africa. This study aims to isolate minor alkaloids present in this plant and assay their cytotoxic activities. Isochondodendrine and 2[prime or minute]-norcocsuline as two minor alkaloids together with the abundant cycleanine were isolated and identified by mass spectrometry and NMR spectroscopy. Both isochondodendrine and 2[prime or minute]-norcocsuline exhibited in vitro cytotoxicity in four ovarian cancer cell lines (A2780, IGROV-1, OVCAR-8, and OVCAR-4) with IC50 ranges of 3.5-17 [small mu ]M and 0.8-6.2 [small mu ]M respectively. These alkaloids showed mostly slightly weaker potencies when tested using normal human ovarian epithelial cells, IC50 = 10.5 +/- 1.2 [small mu ]M and 8.0 +/- 0.2 [small mu ]M for isochondodendrine and 2[prime or minute]-norcocsuline, respectively. The alkaloids induced apoptosis in ovarian cancer cells because they activated caspases 3/7, induced cleavage of PARP, increased the subG1 population in cell cycle analysis and increased Annexin V/propidium iodide staining. These observations suggest that isochondodendrine and 2[prime or minute]-norcocsuline contributing to the cytotoxic activity of T. subcordata may be suitable starting points for the future development of novel therapeutics to treat ovarian cancer

Self-similarity of fluid residence time statistics in a turbulent round jet

Fluid residence time is a key concept in the understanding and design of chemically reacting flows. In order to investigate how turbulent mixing affects the residence time distribution within a flow, this study examines statistics of fluid residence time from a direct numerical simulation (DNS) of a statistically stationary turbulent round jet with a jet Reynolds number of 7290. The residence time distribution in the flow is characterised by solving transport equations for the residence time of the jet fluid and for the jet fluid mass fraction. The product of the jet fluid residence time and the jet fluid mass fraction, referred to as the mass-weighted stream age, gives a quantity that has stationary statistics in the turbulent jet. Based on the observation that the statistics of the mass fraction and velocity are self-similar downstream of an initial development region, the transport equation for the jet fluid residence time is used to derive a model describing a self-similar profile for the mean of the mass-weighted stream age. The self-similar profile predicted is dependent on, but different from, the self-similar profiles for the mass fraction and the axial velocity. The DNS data confirm that the first four moments and the shape of the one-point probability density function of mass-weighted stream age are indeed self-similar, and that the model derived for the mean mass-weighted stream-age profile provides a useful approximation. Using the self-similar form of the moments and probability density functions presented it is therefore possible to estimate the local residence time distribution in a wide range of practical situations in which fluid is introduced by a high-Reynolds-number jet of fluid

A rare duplication on chromosome 16p11.2 is identified in patients with psychosis in Alzheimer's disease

Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis

The poor design of clinical trials of statins in oncology may explain their failure – lessons for drug repurposing

Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an “undruggable” target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug

Effect of Different Prosthetic Knees/feet on the Roll-Over Shape

Roll-over shape (ROS) of knee-ankle-foot (KAF) is a scientific method which has been used to compare performance and design of the different prosthetic foot. In the current study, however, we aimed to understand the influence of the prosthetic components (i.e. knee and foot) on the knee-ankle-foot roll-over shape in a unilateral transfemoral amputee. We performed a case study based on series of experiments with repeated measures on single amputee wearing two different commercially available microprocessor prosthetic knees, during two weeks adaptation period to understand the influence of the prosthetic knee/foot using KAF ROS as an objective measure during level ground walking. The kinematics of the center of pressure (COP), lateral knee and ankle markers were collected and processed to obtain ROS and the results were used to fit a circular shape arc to obtain radius of curvature (ROC). The results indicated that the prosthetic knees have influenced ROC outcomes. The analysis of variance (ANOVA) and post hoc test of the normalized radius of curvature showed the mean of ROC were significantly different between Rheo3 knee, Orion2 and Orion2 with Echelon foot. The amputee reflected his comfort with Rheo3 plus College park foot and Orion with Echelon foot. A conclusion is drawn that multiple comfort zones may exists based on amputee’s ROS metrics. This finding suggests that the design of prosthetic knee should not be considered as a single component but rather as part of a whole system with different comfort zones

Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins