GROWTH INHIBITORY DIXONAPHTHOIMIDAZOLIUMS RELATED TO YM155: SYNTHESIS AND MECHANISTIC INVESTIGATIONS

Ph.DDOCTOR OF PHILOSOPH

Low-frequency incommensurate magnetic response in strongly correlated systems

It is shown that in the t-J model of Cu-O planes at low frequencies the dynamic spin structure factor is peaked at incommensurate wave vectors (1/2+-delta,1/2)$, (1/2,1/2+-delta). The incommensurability is connected with the momentum dependencies of the magnon frequency and damping near the antiferromagnetic wave vector. The behavior of the incommensurate peaks is similar to that observed in La_{2-x}(Ba,Sr)_xCuO_{4+y} and YBa_2Cu_3O_{7-y}: for hole concentrations 0.02<x<=0.12 we find that delta is nearly proportional to x, while for x>0.12 it tends to saturation. The incommensurability disappears with increasing temperature. Generally the incommensurate magnetic response is not accompanied by an inhomogeneity of the carrier density.Comment: 4 pages, 4 figure

First order quantum phase transitions

Quantum phase transitions have been the subject of intense investigations in the last two decades [1]. Among other problems, these phase transitions are relevant in the study of heavy fermion systems, high temperature superconductors and Bose-Einstein condensates. More recently there is increasing evidence that in many systems which are close to a quantum critical point (QCP) different phases are in competition. In this paper we show that the main effect of this competition is to give rise to inhomogeneous behavior associated with quantum first order transitions. These effects are described theoretically using an action that takes into account the competition between different order parameters. The method of the effective potential is used to calculate the quantum corrections to the classical functional. These corrections generally change the nature of the QCP and give rise to interesting effects even in the presence of non-critical fluctuations. An unexpected result is the appearance of an inhomogeneous phase with two values of the order parameter separated by a first order transition. Finally, we discuss the universal behavior of systems with a weak first order zero temperature transition in particular as the transition point is approached from finite temperatures. The thermodynamic behavior along this line is obtained and shown to present universal features.Comment: 7 pages, 5 figures. Invited talk at ICM2006, Kyoto. To appear in JMM

Resonance peak in underdoped cuprates

The magnetic susceptibility measured in neutron scattering experiments in underdoped YBa$_2$Cu$_3$O$_{7-y}$ is interpreted based on the self-consistent solution of the t-J model of a Cu-O plane. The calculations reproduce correctly the frequency and momentum dependencies of the susceptibility and its variation with doping and temperature in the normal and superconducting states. This allows us to interpret the maximum in the frequency dependence -- the resonance peak -- as a manifestation of the excitation branch of localized Cu spins and to relate the frequency of the maximum to the size of the spin gap. The low-frequency shoulder well resolved in the susceptibility of superconducting crystals is connected with a pronounced maximum in the damping of the spin excitations. This maximum is caused by intense quasiparticle peaks in the hole spectral function for momenta near the Fermi surface and by the nesting.Comment: 9 pages, 6 figure

Tyrosine kinase inhibitors for the therapy of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease

Yeast Prions: Protein Aggregation Is Not Enough

Although many proteins -- both damaged and normal -- have a tendency to aggregate, only some are capable of dividing and propagating. What does it take to turn a protein aggregate into an infectious prion

Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

Cabozantinib in progressive medullary thyroid cancer

Purpose Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. Patients and Methods We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. Results The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. Conclusion Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. Conclusions: We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78131/1/thy.2009.0110.pd