Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

<p>Abstract</p> <p>Background</p> <p>Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging.</p> <p>Methods</p> <p>Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm³). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment.</p> <p>Results</p> <p>After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm³) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0.</p> <p>Conclusions</p> <p>As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.</p

Place preference induced by nucleus accumbens amphetamine is impaired by local blockade of Group II metabotropic glutamate receptors in rats

BACKGROUND: The nucleus accumbens (NAc) plays a critical role in amphetamine-produced conditioned place preference (CPP). In previous studies, NAc basal and amphetamine-produced DA transmission was altered by Group II mGluR agents. We tested whether NAc amphetamine CPP depends on Group II mGluR transmission. RESULTS: NAc injections (0.5 μl/side) of the Group II mGluR antagonist (2 S)- a-ethylglutamic acid (EGLU: 0.01–0.8 μg but not 0.001 μg) impaired CPP. The drug did not block the acute locomotor effect of amphetamine. CONCLUSION: Results suggest that Group II mGluRs may be necessary for the establishment of NAc amphetamine-produced CPP. These receptors may also mediate other forms of reward-related learning dependent on this structure

A new 2D-based method for myocardial velocity strain and strain rate quantification in a normal adult and paediatric population: assessment of reference values

<p>Abstract</p> <p>Background</p> <p>Recent advances in technology have provided the opportunity for off-line analysis of digital video-clips of two-dimensional (2-D) echocardiographic images.</p> <p>Commercially available software that follows the motion of cardiac structures during cardiac cycle computes both regional and global velocity, strain, and strain rate (SR).</p> <p>The present study aims to evaluate the clinical applicability of the software based on the tracking algorithm feature (studied for cardiology purposes) and to derive the reference values for longitudinal and circumferential strain and SR of the left ventricle in a normal population of children and young adults.</p> <p>Methods</p> <p>45 healthy volunteers (30 adults: 19 male, 11 female, mean age 37 ± 6 years; 15 children: 8 male, 7 female, mean age 8 ± 2 years) underwent transthoracic echocardiographic examination; 2D cine-loops recordings of apical 4-four 4-chamber (4C) and 2-chamber (2C) views and short axis views were stored for off-line analysis.</p> <p>Computer analyses were performed using specific software relying on the algorithm of optical flow analysis, specifically designed to track the endocardial border, installed on a Windows™ based computer workstation. Inter and intra-observer variability was assessed.</p> <p>Results</p> <p>The feasibility of measurements obtained with tissue tracking system was higher in apical view (100% for systolic events; 64% for diastolic events) than in short axis view (70% for systolic events; 52% for diastolic events). Longitudinal systolic velocity decreased from base to apex in all subjects (5.22 ± 1.01 vs. 1.20 ± 0.88; p < 0.0001). Longitudinal strain and SR significantly increased from base to apex in all subjects (-12.95 ± 6.79 vs. -14.87 ± 6.78; p = 0.002; -0.72 ± 0.39 vs. -0.94 ± 0.48, p = 0.0001, respectively). Similarly, circumferential strain and SR increased from base to apex (-21.32 ± 5.15 vs. -27.02 ± 5.88, p = 0.002; -1.51 ± 0.37 vs. -1.95 ± 0.57, p = 0.003, respectively).</p> <p>Values of global systolic SR, both longitudinal and circumferential, were significantly higher in children than in adults (-1.3 ± 0.2, vs. -1.11 ± 0.2, p = 0.006; -1.9 ± 0.6 vs. -1.6 ± 0.5, p = 0.0265, respectively). No significant differences in longitudinal and circumferential systolic velocities were identified for any segment when comparing adults with children.</p> <p>Conclusion</p> <p>This 2D based tissue tracking system used for computation is reliable and applicable in adults and children particularly for systolic events. Measured with this technology, we have established reference values for myocardial velocity, Strain and SR for both young adults and children.</p

Decoupling property of the supersymmetric Higgs sector with four doublets

In supersymmetric standard models with multi Higgs doublet fields, selfcoupling constants in the Higgs potential come only from the D-terms at the tree level. We investigate the decoupling property of additional two heavier Higgs doublet fields in the supersymmetric standard model with four Higgs doublets. In particular, we study how they can modify the predictions on the quantities well predicted in the minimal supersymmetric standard model (MSSM), when the extra doublet fields are rather heavy to be measured at collider experiments. The B-term mixing between these extra heavy Higgs bosons and the relatively light MSSM-like Higgs bosons can significantly change the predictions in the MSSM such as on the masses of MSSM-like Higgs bosons as well as the mixing angle for the two light CP-even scalar states. We first give formulae for deviations in the observables of the MSSM in the decoupling region for the extra two doublet fields. We then examine possible deviations in the Higgs sector numerically, and discuss their phenomenological implications.Comment: 26 pages, 24 figures, text sligtly modified,version to appear in Journal of High Energy Physic

Vacuum stability and perturbativity of SU(3) scalars

We calculate the vacuum stability conditions and renormalisation group equations for the extensions of standard model with a higher colour multiplet scalar up to the representation 1 5 0 that leaves the strong interaction asymptotically free. In order to find the vacuum stability conditions, we calculate the orbit spaces for the self-couplings of the higher multiplets, which for the representations 1 5 and 1 5 0 of SU(3)(c) are highly complicated. However, if the scalar potential is linear in orbit space variables, it is sufficient to know the convex hull of the orbit space. Knowledge of the orbit spaces also facilitates the minimisation of the potentials. In contrast to the self-couplings of other multiplets, we find that the scalar quartic couplings of the representations 3 and 8 walk rather than run, remaining nearly constant and perturbative over a vast energy range. We describe the conditions for walking couplings using a schematic model. With these technical results at hand we revise earlier results of generation of new scales with large SU(3) c scalar multiplets. Our results are easily extendable to models of new physics with additional SU(3) or SU(N) gauge symmetries.Peer reviewe

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction

Extensive neuroadaptive changes in cortical gene-transcript expressions of the glutamate system in response to repeated intermittent MDMA administration in adolescent rats

<p>Abstract</p> <p>Background</p> <p>Many studies have focused on the implication of the serotonin and dopamine systems in neuroadaptive responses to the recreational drug 3,4-methylenedioxy-metamphetamine (MDMA). Less attention has been given to the major excitatory neurotransmitter glutamate known to be implicated in schizophrenia and drug addiction. The aim of the present study was to investigate the effect of repeated intermittent MDMA administration upon gene-transcript expression of the glutamate transporters (EAAT1, EAAT2-1, EAAT2-2), the glutamate receptor subunits of AMPA (GluR1, GluR2, GluR3), the glutamate receptor subunits of NMDA (NR1, NR2A and NR2B), as well as metabotropic glutamate receptors (mGluR1, mGluR2, mGluR3, mGluR5) in six different brain regions. Adolescent male Sprague Dawley rats received MDMA at the doses of 3 × 1 and 3 × 5 mg/kg/day, or 3× vehicle 3 hours apart, every 7^thday for 4 weeks. The gene-transcript levels were assessed using real-time PCR validated with a range of housekeeping genes.</p> <p>Results</p> <p>The findings showed pronounced enhancements in gene-transcript expression of GluR2, mGluR1, mGluR5, NR1, NR2A, NR2B, EAAT1, and EAAT2-2 in the cortex at bregma +1.6. In the caudate putamen, mRNA levels of GluR3, NR2A, and NR2B receptor subunits were significantly increased. In contrast, the gene-transcript expression of GluR1 was reduced in the hippocampus. In the hypothalamus, there was a significant increase of GluR1, GluR3, mGluR1, and mGluR3 gene-transcript expressions.</p> <p>Conclusion</p> <p>Repeated intermittent MDMA administration induces neuroadaptive changes in gene-transcript expressions of glutamatergic NMDA and AMPA receptor subunits, metabotropic receptors and transporters in regions of the brain regulating reward-related associative learning, cognition, and memory and neuro-endocrine functions.</p

The Biodiversity of the Mediterranean Sea: Estimates, Patterns, and Threats

The Mediterranean Sea is a marine biodiversity hot spot. Here we combined an extensive literature analysis with expert opinions to update publicly available estimates of major taxa in this marine ecosystem and to revise and update several species lists. We also assessed overall spatial and temporal patterns of species diversity and identified major changes and threats. Our results listed approximately 17,000 marine species occurring in the Mediterranean Sea. However, our estimates of marine diversity are still incomplete as yet—undescribed species will be added in the future. Diversity for microbes is substantially underestimated, and the deep-sea areas and portions of the southern and eastern region are still poorly known. In addition, the invasion of alien species is a crucial factor that will continue to change the biodiversity of the Mediterranean, mainly in its eastern basin that can spread rapidly northwards and westwards due to the warming of the Mediterranean Sea. Spatial patterns showed a general decrease in biodiversity from northwestern to southeastern regions following a gradient of production, with some exceptions and caution due to gaps in our knowledge of the biota along the southern and eastern rims. Biodiversity was also generally higher in coastal areas and continental shelves, and decreases with depth. Temporal trends indicated that overexploitation and habitat loss have been the main human drivers of historical changes in biodiversity. At present, habitat loss and degradation, followed by fishing impacts, pollution, climate change, eutrophication, and the establishment of alien species are the most important threats and affect the greatest number of taxonomic groups. All these impacts are expected to grow in importance in the future, especially climate change and habitat degradation. The spatial identification of hot spots highlighted the ecological importance of most of the western Mediterranean shelves (and in particular, the Strait of Gibraltar and the adjacent Alboran Sea), western African coast, the Adriatic, and the Aegean Sea, which show high concentrations of endangered, threatened, or vulnerable species. The Levantine Basin, severely impacted by the invasion of species, is endangered as well