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J Rak

Publications and source records attributed to J Rak.

At least 19 recordsLinked to original sources
PubMed2006

Leptonic and charged kaon decay modes of the phi meson measured in heavy-ion collisions at the CERN super proton synchrotron.

We report on results of a measurement of meson production in central Pb-Au collisions at E(lab) = 158A GeV. For the first time in the history of high energy heavy-ion collisions, phi mesons were reconstructed both in the K+K- and the dilepton decay channels in the same experiment. This measurement yields rapidity densities near midrapidity, from the two decay channels, of 2.05 +/- 0.14(stat) +/- 0.25(syst) and 2.04 +/- 0.49(stat) +/- 0.32(syst), respectively. The shape of the measured transverse momentum spectrum is also in close agreement in both decay channels. The data rule out a possible enhancement of the phi yield in the leptonic over the hadronic decay channel of a factor 1.6 or larger at the 95% C.L. This rules out the discrepancy reported in the literature between measurements of the hadronic and dimuon decay channels by two different experiments.

Journal Article↗
PubMed2006

A disconnect between antitumor and antiangiogenic effects of fluvastatin in vitro and in vivo.

The possible role of statins in cancer is controversial. Indeed, among the multiplicity of biological effects ascribed to these widely used cholesterol lowering agents some could, at least in theory, inhibit tumor growth (e.g. by inhibiting Ras oncoproteins), while other actions are inert, or may even stimulate cancer aggressiveness (e.g. through promoting neovascularization). In order to address some of these controversies, we set out to compare the effects of statins on growth of cancer and endothelial cells in vitro, to the impact of these drugs on angiogenesis-dependent expansion of the corresponding tumors in vivo. Water-soluble fluvastatin was used at concentrations (0-800 ng/ml) against human umbilical vein endothelial cells (HUVEC), and several well-characterized cancer cell lines in culture, including: carcinoma (LLC), melanoma (B16F1) and fibrosarcoma driven by mutant H-ras (528ras1). Endpoints were based on 3H-thymidine incorporation assay, cell morphology and tumorigenicity in mice. The growth inhibitory effects of fluvastatin varied among cancer cell lines (LLC>B16F1>528ras1), irrespectively of their mutant H-ras status. Fluvastatin also blocked the action of angiogenic factors on cultured endothelial cells, but was relatively ineffective against highly angiogenic and aggressive tumors both in young mice (6-8 weeks), and in less aggressively growing tumors in aged (80-90 weeks) mice. Thus, antitumor and antiangiogenic activity of fluvastatin in vitro is not recapitulated in vivo. Tumors may display a form of resistance to statins through a mechanism operative only in vivo.

Animals↗
PubMed2006

Emerging anticoagulants: mechanism of action and future potential.

Medical needs associated with diverse thromboembolic conditions are not fully met by currently available anticoagulants. Of those, unfractionated heparin (UFH) is gradually replaced by low molecular weight heparin (LMWH) for prevention and treatment of venous thromboembolism and acute coronary syndromes, along with supportive treatment with oral anticoagulants, such as warfarin derivatives. While generally effective these agents have several shortcomings involving compliance, delivery, efficacy and safety considerations in various disease settings, and for these reasons new anticoagulants are sought, to target more specifically the critical effectors and steps in the blood coagulation process, namely: (i) initiation, (ii) propagation and (iii) the phase of thrombin activity. The emerging agents that block tissue factor/factor VIIa-dependent initiation phase of the coagulation cascade, include: recombinant tissue factor pathway inhibitor (rTFPI), nematode anticoagulant peptide (NAPc2), active site-blocked factor VIIa (FVIIai) and TF targeting antibodies. Some of them are currently evaluated in clinical trials with promising results. Propagation phase of thrombus formation (e.g. the activity of factors IXa, Xa, VIIIa or Va) is targeted mainly by various indirect, direct and bimodal inhibitors, such as fondaparinux, indraparinux, tick anticoagulant peptide (TAP), antistatin (ANT) and antithrombin-heparin covalent complex (ATH), all endowed mostly with an anti-Xa activity. Although promising, some of these agents (TAP, ANT and ATH) have not progressed beyond animal testing while others (fondaparinux) was already assessed for prevention and treatment of venous thromboembolism and for treatment of arterial thrombosis. Lastly, inhibitors of thrombin activity are composed of either indirect (UFH, LMWH), or direct thrombin (FIIa) inhibitors including: hirudin, argatroban, melagatran, ximelagatran, dabigatran, and bivalirudin. These agents are either in advanced development or already approved for clinical use. Bimodal FIIa inhibitory activity of ATH was demonstrated in animal models of venous and arterial thrombosis, but is in need of further development. In conclusion, while some of these emerging anticoagulants, such as fondaparinux, idraparinux, ximelagatran and ATH appear to possess superior efficacy-safety profile, as compared to their conventional predecessors (UFH, LMWH and warfarin), their cost-effectiveness, side effects and antidote availability have to be considered. More importantly, coagulation factors that are targets of these inhibitory activities also affect coagulation independent processes, such as wound healing, inflammation, angiogenesis, mitogenesis and cell survival. Thus the consequences of both coagulation-dependent and -independent effects of new agents should be carefully considered before proper clinical indications are established.

Anticoagulants↗
PubMed2006

Genetic determinants of cancer coagulopathy, angiogenesis and disease progression.

Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that may be relevant to therapeutic efficacy of these drugs. We also postulate that since TF is the oncogene target, circulating TF (microparticles) could serve as surrogate marker of the biological activity oncogene-directed agents exert in vivo. Thus, both genetic and epigenetic factors appear to conspire to activate various components of the hemostatic system in cancer patients, both locally and systemically. These activities act as mediators of cancer coagulopathy, angiogenesis, metastasis and other events involved in disease progression and should be recognized in designing better anticancer therapies.

Animals↗
PubMed2005

Heparin compromises streptokinase-induced arterial patency in rabbits.

INTRODUCTION: Little is known with regard to efficacy of heparin as an adjunct to fibrinolytics under conditions of severe vascular damage. In this study, we compared the effects of unfractionated heparin (UH), low-molecular weight heparin (LMWH), and recombinant desulfohirudin (HIR) in combination with streptokinase (SK) in such settings. MATERIALS AND METHODS: We used an established rabbit model, in which thrombosis, critical stenosis, and vascular wall damage were introduced to a segment of the abdominal aorta and the effects of the respective therapies were assessed by time to patency (TTP in minutes), cumulative patency (CP (%)), lysis of original clot (CL (%)), and net clot accretion (NCA (%)). Treatments were administered over 90 min at the following doses: SK: 33,000 U/kg, UH: 125-250 U/kg, LMWH: 1.25-2.5 mg/kg, HIR: 0.25-0.55 mg/kg. RESULTS: Unexpectedly, UH and LMWH had a paradoxical and detrimental effect on SK-mediated recanalization as measured by both TTP and CP. Thus, administration of SK vs. SK+UH or SK+LMWH resulted in TTP values of 43+/-8 min vs. 70+/-11 min (p<0.05) and 67+/-12 min. (p<0.08), respectively. For CP, the corresponding values were 21+/-7%, 0.5+/-0.3% and 9+/-8%. This delay in vessel recanalization occurred despite excessive systemic anticoagulation (activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) ratios >6 and >34, respectively). Of interest, both heparinoids completely inhibited SK-induced fibrinogen consumption (FC). In contrast, recombinant desulfohirudin (HIR) shortened SK-induced TTP (4.97+/-0.81 min) without preserving fibrinogen. CONCLUSIONS: Our findings suggest that caution needs to be exercised, when using the combination of SK and heparinoids for the treatment of arterial thrombosis under conditions of severe vascular damage and stenosis.

Animals↗
PubMed2004

Interferometry of direct photons in central 208Pb + 208Pb collisions at 158A GeV.

Two-particle correlations of direct photons were measured in central 208Pb+208Pb collisions at 158A GeV. The invariant interferometric radii were extracted for 100<K(T)<300 MeV/c and compared to radii extracted from charged pion correlations. The yield of soft direct photons, K(T)<300 MeV/c, was extracted from the correlation strength and compared to theoretical calculations.

Journal Article↗
PubMed2004

Origin of chemiluminescence accompanying the reaction of the 9-cyano-10-methylacridinium cation with hydrogen peroxide.

The 9-cyano-10-methylacridinium cation possesses an electrophilic center at the carbon atom in position (9) susceptible to the addition of anions. The addition of OOH(-) to this cation--in weakly acidic, neutral, or alkaline media--initiates processes leading to the formation of electronically excited 10-methyl-9-acridinone, which deactivates by light emission. The effect of changes in reactant concentrations and pH on emission decay with time, as well as other features of the accompanying chemiluminescence, were established. Calculations carried out at the semiempirical and density functional theory level demonstrated that initial addition of OOH(-) and subsequent processes lead either to the elimination of OCNH (in weakly acidic and neutral media) or OCN(-) (in alkaline media) and that their exothermicity is sufficiently high to generate electronically excited 10-methyl-9-acridinone. On the other hand, primary addition of OH(-) to C(9) in alkaline media initiates the conversion of the cation to the nonexcited 10-methyl-9-acridinone. This relatively rapid process influences to a substantial extent the intensity of the chemiluminescence. The prospects for the analytical application of 9-cyano-10-methylacridinium salts are briefly outlined.

Journal Article↗
PubMed2004

Semihard scattering unraveled from collective dynamics by two-pion azimuthal correlations in 158A GeV/c Pb+Au collisions.

Elliptic flow and two-particle azimuthal correlations of charged hadrons and high-p(T) pions (p(T)>1 GeV/c) have been measured close to midrapidity in 158A GeV/c Pb+Au collisions by the CERES experiment. Elliptic flow (v(2)) rises linearly with p(T) to a value of about 10% at 2 GeV/c. Beyond p(T) approximately 1.5 GeV/c, the slope decreases considerably, possibly indicating a saturation of v(2) at high p(T). Two-pion azimuthal anisotropies for p(T)>1.2 GeV/c exceed the elliptic flow values by about 60% in midcentral collisions. These nonflow contributions are attributed to nearside and back-to-back jetlike correlations, the latter exhibiting centrality dependent broadening.

Journal Article↗
PubMed2003

Enhanced production of low-mass electron-positron pairs in 40-AGeV Pb-Au collisions at the CERN SPS.

We report on first measurements of low-mass electron-positron pairs in Pb-Au collisions at the CERN SPS beam energy of 40 AGeV. The observed pair yield integrated over the range of invariant masses 0.2 e(+)e(-) annihilation with a modified rho propagator. They may be linked to chiral symmetry restoration and support the notion that the in-medium modifications of the rho are more driven by baryon density than by temperature.

Journal Article↗
PubMed2003

Universal pion freeze-out in heavy-ion collisions.

Based on an evaluation of data on pion interferometry and on particle yields at midrapidity, we propose a universal condition for thermal freeze-out of pions in heavy-ion collisions. We show that freeze-out occurs when the mean free path of pions lambda(f) reaches a value of about 1 fm, which is much smaller than the spatial extent of the system at freeze-out. This critical mean free path is independent of the centrality of the collision and beam energy from the Alternating Gradient Synchrotron to the Relativistic Heavy Ion Collider.

Journal Article↗
PubMed2003

The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.

Although hirudin is better than heparin at preventing recurrent ischemia in patients with unstable angina, hirudin produces more bleeding. The purpose of this study was to use a rabbit arterial thrombosis prevention and ear bleeding model to determine whether for equivalent efficacy, melagatran, a synthetic direct thrombin inhibitor, is safer than hirudin. A combination of balloon injury and stasis was used to induce thrombosis in the distal aorta, and patency and blood flow were continuously monitored with ultrasonic flow probes. Rabbits were randomized to melagatran (in total doses of 78-313 nmol kg(-1)), hirudin (in total doses of 18-107 nmol kg(-1)), or saline over 90 min. To assess safety, blood loss from standardized ear incisions was measured. Both melagatran and hirudin produced dose-dependent increases in patency and blood flow. At doses that maintained the highest levels of patency, however, melagatran produced 2-3-fold less bleeding than hirudin. Thus, at maximally effective doses, melagatran causes less bleeding than hirudin in this model. These findings raise the possibility that some direct thrombin inhibitors are safer than others.

Animals↗
PubMed2003

[Rheologic properties of Vivastar P 5000 hydrogel].

Within the framework of pre-formulation studies, the paper evaluates the rheological properties of hydrogels whose gel-forming substance is a polymer supplied by the firm J. Rettenmaier & SöhneGMBH + CO. It is VIVASTAR P 5000, a modified derivate of carboxymethyl starch. The evaluation of rheological properties included hydrogels with 1.5, 2.0 and 2.5 w % of VIVASTAR P 5000. The highest viscosity was shown by the hydrogel with 2.0% concentration of the polymer. The system without and with the model drug with a local anaesthetic effect was thixotropic. From the viewpoint of topical administration, VIVASTAR P 5000 in 2.0% is optimal for hydrogel formulation.

Hydrogels↗
PubMed2002

[Liberation of potential local anesthetics from colloidal dispersions].

Evaluation of pharmaceutical availability of drugs from topical preparations is usually aimed to evaluate the capability of the dosage form to release the drug for its therapeutic action. Permeation cells have been used for this purpose, employing solid membranes including cellophane. Within a study of phenylcarbamic acid derivatives with local anaesthetic effect, the present paper evaluates the dosage form for topical administration containing potential drug XIX M, the chemical name N-[2-(2-heptyloxyphenylcarbamoyloxy)-ethyl]-morpholinium chloride and potential drug XXII B, the chemical name N-[2-(2-octyloxyphenylcarbamoyloxy)-ethyl]-dimethylammonium chloride. The selected auxiliary substance in the formulation of the dosage form was a cellulose derivative--methylcellulose in increasing concentrations from 0.5 to 1.5%. On the basis of the obtained results it can be stated that the examined polymer methylcellulose with increasing concentration decelerated the release of both potential drugs approximately in the same way and that it can be used in practice to prolong the local anaesthetic effect.

Anesthetics, Local↗
PubMed2001

Low-energy tautomers and conformers of neutral and protonated arginine.

The relative stabilities of zwitterionic and canonical forms of neutral arginine and of its protonated derivative were studied by using ab initio electronic structure methods. Trial structures were first identified at the PM3 level of theory with use of a genetic algorithm to systematically vary geometrical parameters. Further geometry optimizations of these structures were performed at the MP2 and B3LYP levels of theory with basis sets of the 6-31++G** quality. The final energies were determined at the CCSD/6-31++G** level and corrected for thermal effects determined at the B3LYP level. Two new nonzwitterionic structures of the neutral were identified, and one of them is the lowest energy structure found so far. The five lowest energy structures of neutral arginine are all nonzwitterionic in nature and are clustered within a narrow energy range of 2.3 kcal/mol. The lowest energy zwitterion structure is less stable than the lowest nonzwitterion structure by 4.0 kcal/mol. For no level of theory is a zwitterion structure suggested to be the global minimum. The calculated proton affinity of 256.3 kcal/mol and gas-phase basicity of 247.8 kcal/mol of arginine are in reasonable agreement with the measured values of 251.2 and 240.6 kcal/mol, respectively. The calculated vibrational characteristics of the low-energy structures of neutral arginine provide an alternative interpretation of the IR-CRLAS spectrum (Chapo et al. J. Am. Chem. Soc. 1998, 120, 12956-12957).

Algorithms↗
PubMed2001

Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis.

Inhibitors of epidermal growth factor receptor (EGFR) signaling are among the novel drugs showing great promise for cancer treatment in the clinic. However, the possibility of acquired resistance to such drugs because of tumor cell genetic instabilities has not yet been explored. Here we report the experimental derivation and properties of such cell variants obtained from recurrent tumor xenografts of the human A431 squamous cell carcinoma, after two consecutive cycles of therapy with one of three different anti-EGFR monoclonal antibodies: mR3, hR3, or C225. Initial response to a 2-week period of treatment was generally total tumor regression and was not significantly different among the three antibody groups. However, tumors often reappeared at the site of inoculation, generally after prolonged latency periods, and most of the tumors became refractory to a second round of therapy. Cell lines established from such resistant tumors retained high EGFR expression, normal sensitivity to anti-EGFR antibody or ligand, and unaltered growth rate when compared with the parental line in vitro. In contrast, the A431 cell variants exhibited an accelerated growth rate and a significantly attenuated response to anti-EGFR antibodies in vivo relative to the parental line. Because of the reported suppressive effect of EGFR inhibitors on vascular endothelial growth factor (VEGF) expression, and the demonstrated role of VEGF in the angiogenesis and growth of A431 tumor xenografts, relative VEGF expression was examined. Five of six resistant variants expressed increased levels of VEGF, which paralleled an increase in both angiogenic potential in vitro and tumor angiogenesis in vivo. In addition, elevated expression of VEGF in variants of A431 cells obtained by gene transfection rendered the cells significantly resistant to anti-EGFR antibodies in vivo. Taken together, the results suggest that, at least in the A431 system, variants displaying acquired resistance to anti-EGFR antibodies can emerge in vivo and can do so, at least in part, by mechanisms involving the selection of tumor cell subpopulations with increased angiogenic potential.

Animals↗
PubMed2001

RB2/p130 gene-enhanced expression down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in vivo.

Angiogenesis is an essential step in the progression of tumor formation and development. The switch to an angiogenetic phenotype can occur as a distinct step before progression to a neoplastic phenotype and is linked to genetic changes such as mutations in key cell cycle regulatory genes. The pathogenesis of the angiogenetic phenotype may involve the inactivation of tumor suppressor genes such as the "guardian of the genome," p53, and the cyclin-dependent kinase inhibitor p16. Retinoblastoma family member RB2/p130 encodes a cell cycle regulatory protein and has been found mutated in different tumor types. Overexpression of RB2/p130 not only suppresses tumor formation in nude mice but also causes regression of established tumor grafts, suggesting that RB2/p130 may modulate the angiogenetic balance. We found that induction of RB2/p130 expression using a tetracycline-regulated gene expression system as well as retroviral and adenoviral-mediated gene delivery inhibited angiogenesis in vivo. This correlated with pRb2/p130-mediated down-regulation of vascular endothelial growth factor protein expression both in vitro and in vivo.

Animals↗
PubMed2001

Ras regulation of vascular endothelial growth factor and angiogenesis.

Given the multifaceted role of Ras in tumor angiogenesis, pharmacologic targeting of such proteins may bring about at least three important consequences: (1) partial obliteration of the angiogenic competence of tumor cells, (2) an increase in vascular dependence and sensitization to apoptosis, and (3) a direct inhibition of endothelial cell responses to proangiogenic stimuli. Exploration of some of these possibilities, using various pharmacological compounds and antibodies, has already begun. An intriguing possibility is that Ras antagonists and signal transduction inhibitors may synergize with a number of other antiangiogenic modalities such as direct acting antiangiogenic agents (e.g., endostatin) or antivascular regimens involving low-dose continuous chemotherapy as a vasculature-targeting strategy.

3T3 Cells↗