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[Image: see text] On the basis of the knowledge that the proline-rich hot spot PPPRPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22(phox) (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47(phox) (p47), we designed a mimetic of the tripeptide PPP based on NMR and X-ray crystallographic data for the p22(151−161) peptide PPSNPPPRPPA with a peptide construct. Incorporation of the synthetic pseudo-triproline mimetic Pro-Pro-Cyp in a molecule derived from molecular modeling studies led to only a 7-fold diminution in activity in a surface plasmon resonance assay relative to the same molecule containing the natural Pro-Pro-Pro tripeptide. The alternative sequence corresponding to a Pro-Cyp-Pro insertion was inactive. This is a first example of the use of a triproline mimetic to interfere with the formation of the p47–p22 complex, which is critical for the activation of NOX, leading to the production of reactive oxygen species as superoxide anions.

Pharmacokinetic parameters of S49076 administered orally to female balb/c nu/nu mice

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

Western blot detection of total and phosphorylated MET, AXL, FGFR1/2/3 and phosphorylated FRS2 in cell lines and tumor xenografts used in the study

Supplementary Figure Legends

Absztrakt: Bevezetés: Az Egészségügyi Világszervezet adatai szerint 1,3 milliárd ember él a látásgyengeség valamilyen formájával, melynek mintegy 80%-a megelőzhető lenne. Kutatások alátámasztják, hogy a látás csökkenése befolyásolja az életminőséget, és megrövidíti a várható élettartamot. Célkitűzés: A Szegedi Tudományegyetem több klinikájának együttműködésével zajló, a 40 és 80 év közötti életkorú, dél-magyarországi lakosság körében végzett felmérés (OTKA-NN-110932) szemészeti vizsgálati eredményeinek rögzítése és ezek életminőséget befolyásoló hatásainak elemzése. Módszer: Az Országos Tudományos Kutatási Alap által finanszírozott keresztmetszeti kutatási programban összesen 731, 40 és 80 év közötti személy vett részt. A bevont 731 alanyból 717 fő (397 nő és 320 férfi) vett részt teljes körű szemészeti vizsgálaton és töltötte ki a NEI-VFQ-25 honosított kérdőívet. A statisztikai analízishez egy szempontos ANOVA- és Mann–Whitney-próbát használtunk. A szignifikancia szintjeként a pEredmények: A vizsgálatban részt vevő személyeket 4 korcsoportra osztottuk: 1) 40–50 év, 2) 51–60 év, 3) 61–70 év, 4) 71–80 év. A szemszárazság, a lencsehomályok előfordulása, a szemüvegviselés, az időskori maculadegeneratióra utaló eltérések jelenléte az életkor előrehaladtával nőtt. A NEI-VFQ-25 kérdőív alskálái az életminőség romlását mutatják a kor növekedésével és a szemészeti eltérések előfordulási gyakoriságának fokozódásával összefüggésben. Következtetés: A látás, mint a külvilág észlelésének meghatározó lehetősége, kiemelkedő helyet foglal el az életminőséget befolyásoló tényezők között. Kutatásunk tendenciái mutatják, hogy a látással kapcsolatos életminőséget jelző értékek a kor előrehaladtával hogyan csökkennek. Ezért is tekintjük szükségesnek az idősebb populáció rendszeres ellenőrzését, felismerendő és lehetőség szerint kiküszöbölendő az életminőséget negatívan befolyásoló tényezőket. Orv Hetil. 2020; 161(43): 1824–1830.

Keratitis due to Candida parapsilosis or Corynebacterium macginleyi is uncommon. We present a patient with several risk factors who suffered two subsequent corneal infections caused by these pathogens and healed with topical conservative therapy. The important factor was the early detection of infection. Fluconazole solution administered topically as eye drops combined with regular debridement proved in this case a successful alternative to systemic antifungal treatment. With a perceived recurrence of the keratitis, one must take into account the involvement of other pathogens present. The previous use of an antifungal solution other than a conventional eye drop could be an additional risk factor for a second bacterial infection, but the benefits should still rule in favor of such a treatment.

Objective: To assess the utility of visual electrophysiological methods, visual evoked potentials (VEPs) and pattern electroretinograms (PERGs) were recorded for the detection of subclinical optic nerve and retinal involvement in patients with diabetes mellitus. Subjects and Methods: The data of 63 patients (126 eyes) with no vascular retinopathy or optic neuropathy were retrospectively analyzed. The patients were divided into polyneuropathic/nonpolyneuropathic groups to differentiate between early and late subclinical stages. The recorded parameters were compared with local reference values. Results: 116 eyes (92%) had VEP and 76 (60%) had PERG abnormalities. The most frequent alteration was latency delay, but waveform and amplitude irregularities were also observed. The simultaneous use of the two methods allowed us to differentiate abnormal VEPs of purely optic nerve origin from those reflecting retinal involvement. Conclusions: We suggest that regular electrophysiological screening should receive more attention in the ophthalmological care of diabetic patients.

Dirofilariasis is an emerging zoonosis (supported by climate change) in Central Europe. Human infections are usually caused by Dirofilaria repens and Dirofilaria immitis with mediation of mosquito vectors. Aims of this publication were to report our dirofilariasis cases, and to summarize Hungarian epidemiological data by reviewing literature. We present five (four ophthalomological, one subcutaneous) cases observed within a 2-year period in Southern Hungary. Ages of infected patients were between 31 and 74 years. First case during pregnancy is also reported. There was no travel history in the anamnesis of patients which could explain acquisition of the infection. Moving, intact worms eliminated by surgical interventions were identified on the basis of morphological features as D. repens. Since the first report of human case, 115 further episodes (in addition to ours) were diagnosed in Hungary. Mean age of the patients was 47 years. Reviewing national reports, the ratio of subcutaneous infections was higher than that of the ocular ones (66 and 45, respectively). Evaluation of the territorial distribution of human episodes revealed that most infections occurred in patients living in the Danube–Tisza interfluvial region and eastern part of the country. However, sporadic cases were also found in western counties during 2014. Most of the Hungarian dirofilariasis cases were autochthonous infections. Occurrence in the western counties may suggest the spreading of this emerging zoonosis to these areas. Comprehensive monitoring and data analysis are desirable, therefore reporting the epidemiologic data in the case of human infections should be made mandatory.

PURPOSE To determine the normal interocular differences in amplitudes and peak times of the pattern electroretinograms (PERGs) and pattern visual evoked potentials (PVEPs) and to investigate whether the PERG and PVEP parameters correspond in lateral dominance or whether the eye-side distributions of the functional parameters are similar. METHODS The PERGs and PVEPs were recorded in healthy subjects (N = 77) according to the standards of the International Society for Clinical Electrophysiology of Vision, with the modification of the check size of the PERG to 0.5 degrees. This allows stimulation of the macular ganglion cells and their corresponding visual pathways in healthy subjects. RESULTS Comparison of the averaged higher and lower response amplitudes and the shorter and longer response peak times showed significant differences (p < 0.001) in both the PERG and the PVEP parameters (median [5 to 95%]): the P50 (1.92% [0 to 5.48%]) and N95 (2.06% [0 to 13.95%]) peak times and the P50 (11.82% [1.32 to 29.93%) and N95 (9.45% [1.17 to 30.38%]) amplitudes of the PERGs and the P100 (1.04% [0 to 4.15%]) and N135 (1.96% [0 to 12.36%]) peak times and the P100 (9.86% [1.26 to 29.76%]) and N135 (11.19% [1.18 to 29.99%]) amplitudes of the PVEPs. No significant correlation was found concerning the eye dominance of the PERG and PVEP parameters. CONCLUSIONS Our results reveal a significant interocular difference on PERG and PVEP recording, but this could not be ascribed to the anatomy of the retina and related visual pathways. If the difference between the eyes is not taken into account, misinterpretation may occur in a pathological process.

Purpose: To compare the interocular amplitude differences of the multifocal electroretinograms (mfERGs) evoked by either monocular or binocular stimulation in healthy subjects with good vision. Methods: Thirty-five subjects were included in the study. A Roland Consult RETIscan system was used. DTL electrodes were employed. First, the right and left eyes were stimulated separately, then, binocular stimulation was applied. The amplitudes of the scalar products were averaged over five concentric retinal regions (rings). Results: The interocular amplitude differences were 21.55% (SD: ±12.72) under monocular conditions and 18.69% (SD: ±11.64) under binocular conditions. No significant differences were found between the amplitudes and variability values obtained under either monocular or binocular stimulation. Conclusions: Our results provided no evidence for the advantage of either binocular or monocular stimulating conditions in obtaining mfERGs. A considerable side difference was found between the mfERGs of ...

We describe a rare case of Lyme disease complicated by unilateral neuroretinitis in the right eye. We report a case of a 27-year-old woman with blurred vision on her right eye. Because of the suspicion of optic neuritis (multiplex sclerosis) neurological examination was ordered. Surprisingly, computer tomography of the brain revealed incomplete empty sella, which generally results not monocular, but bilateral optic nerve swelling. Opthalmological examination (ophthalmoscopy and optical coherence tomography) indicated not only monocular optic nerve, but retinal oedema next to the temporal part of the right optic disk. Visual evoked potentials (VEP) demonstrated no P100 latency delay and mild differences between the amplitudes of the responses of the left and right eye. Optical coherence tomography (OCT) demonstrated the swelling of the optic nerve head and oedematous retina at the temporal part of the disk. Suspicion of an inflammatory cause of visual disturbance blood tests was ordered. Doxycycline treatment was ordered till the result of the blood test arrived. The Western blot and ELISA test were positive for Borrelia burgdorferi sensu lato. Following one week corticosteroide and ceftriaxone treatments, the patient displayed a clinical improvement. Unilateral neuroretinitis with optic disk swelling due to neuroborreliosis is a rare complication and in many cases it is difficult to distinguish between inflammatory and ischemic lesions. Further difficulty in the diagnosis can occur when intracranial alterations such as empty sella is demonstrated by CT examination.

A novel cascade condensation-intramolecular acylation process for the synthesis of the title compounds from anthranilic acid derivatives is developed.

Infertile Hungarian couples were surveyed with regard to their opinion of preconception gender selection by the separation of X- and Y-bearing sperm populations.Self-completion of a questionnaire. Group 1: subjects presenting for infertility examination; Group 2: presenting for homologous intrauterine insemination.As concerns the gender of the firstborn, 13.8% of those in Group 1 preferred a boy and 10.3% a girl, while 75.9% had no preference. The male preference was higher in Group 2: 33.3% preferred a boy and 7.4% a girl while 59.3% had no preference (chi 2, p0.05). In the event of a wish for more offspring, 91% in Group 1 and 94% in Group 2 did not have a wish for only one particular gender. In Group 2, 30.8% were willing to pay the extra costs for a gender selection procedure as compared with only 10.8% of the couples in Group 1 (chi 2, p0.05). If the National Health Fund fully covered the costs, 53.4% in Group 1 and 38.5% in Group 2 would request the procedure for nonmedical reasons, while 94.6% and 97.4% of them, respectively would so for medical reasons.Our findings revealed a trend to preference for firstborn males, although couples wishing more than one offspring prefer equal numbers of male and female children. The utilization of preconception gender selection, therefore, would not seem to appreciably affect the natural male/female ratio. Genetic indications exert significant effects on the decision regarding sex selection procedures.

This study was conducted to determine a possible relationship between regular cell phone use and different human semen attributes. The history-taking of men in our university clinic was supplemented with questions concerning cell phone use habits, including possession, daily standby position and daily transmission times. Semen analyses were performed by conventional methods. Statistics were calculated with SPSS statistical software. A total of 371 were included in the study. The duration of possession and the daily transmission time correlated negatively with the proportion of rapid progressive motile sperm (r = -0.12 and r = -0.19, respectively), and positively with the proportion of slow progressive motile sperm (r = 0.12 and r = 0.28, respectively). The low and high transmitter groups also differed in the proportion of rapid progressive motile sperm (48.7% vs. 40.6%). The prolonged use of cell phones may have negative effects on the sperm motility characteristics.

A total of 274 men (aged: 26 +/- 4.9 years) with normozoospermia were enrolled into this study. Their body mass index (BMI: kg/m2) varied between 17 and 39. According to BMI, the patients were divided into four groups: Group 1: 17-20, Group 2: 20.1-25, Group 3: 25.1-30 and Group 4: 30.1-39. Twenty-nine subjects were found in the first, 96 in the second, 91 in the third and 58 men in the fourth group. Sperm concentration was significantly lower in the obese group (29 x 10(6)/ml, p0.05) than in the group of BMI 17-20, 20-25 and 25-30. In advance, in the obese group, sperm count continuously decreased with aging. We conclude that obesity is associated with a lower sperm count in case of normozoospermia.

The reaction of various anthranilic acid derivatives or their esters with 4-oxotetrahydrothiophene-3-carbonitrile 2, 2-oxocyclopentanecarbonitrile (9, n = 1) or 2-oxocyclohexanecarbonitrile (9, n = 2) in ethanol under reflux conditions giving rise the formation of single products isolated in each case after simple filtration. The products were characterized as pyrazolo[1,5-a]quinazolin-5-ones 4 instead of the expected pyrazol-3-amines 3. These cascade condensation–intramolecular acylation processes generated in one-step reactions from simple starting materials novel heterocyclic scaffolds ready for further functionalization. The present synthetic protocol provides acceptable yields of new tetracyclic products in high purity.

The generation of N-substituted, stabilised azomethine ylides in the presence of N-phenylmaleimide gave the bicyclo[3.3.0] octane-3-carboxylate cycloadducts. In the absence of a dipolarophile, these azomethine ylides gave novel piperazine-6-carboxylates.

The 1,3-dipolar cycloadditions of various azomethine ylides to 2-oxoindolin-3-ylidene derivatives have been investigated. The structure and stereochemistry of cycloadducts were studied in detail by NMR spectroscopic methods.

The tricyclic core of the martinellines has been synthesised stereoselectively in two steps, using 1,3-dipolar cycloaddition of azomethine ylides as a key step.

A new two-step synthesis of pyrrole-2-carboxylic acids, steps via 1,3 dipolar cycloaddition of azomethine ylides to nitro-styrenes and oxidation of the resulting pyrrolidines with alkaline hydrogen peroxide is described. The oxidation of cycloadducts 3 by the means of MnO2 under different conditions also has been examined.

a,b;g,d-Unsaturated nitrile oxides 6, 13 have been prepared from the corresponding aldehydes via sequential oxime formation, chlorination, and dehydrochlorination. These nitrile oxides show unexpected stability, presumably due to delocalisation, and can be isolated. 2,6-Diphenylbenzonitrile oxide 13b was particularly stable and a single crystal X-ray structure was obtained. 3,3-Diphenylpropenitrile oxide 6 was also isolated but could be dimerized, to give a 1,4,2,5-dioxadiazine 7 or furoxan 8, via slight modifications to the conditions employed. The corresponding nitrones 14, 17 have also been prepared, via the reaction of the a,b;g,d-unsaturated aldehydes 10a,b with substituted hydroxylamines, isolated and trapped.

We have studied the behaviour of 2-acetoxy-nitroethane derivatives in the presence of triethylamine and of an azomethine ylide generated also by the action of this base in the same reaction mixture. Under these conditions the nitro-olefins are generated and react in situ with the corresponding dipoles, giving pyrrolidine derivatives in moderate to good yields.

The simple γ-pyranones 4, 5, and 6 undergo 4π + 2π cycloaddition reactions with Danishefsky’s diene 8 and azomethine ylides 12, 16, and 25 to give a range of cycloadducts. The position of the electron-withdrawing group is the decisive factor in these reactions, with the 2-substituted derivatives 5 and 6 being less reactive than the 3-substituted γ-pyranone 4. The esters, 4 and 5, react via addition across the 2,3-CC bond of the pyranone ring, whilst the aldehyde 6 reacts via addition across the CO of the carbaldehyde group.

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749–62. ©2013 AACR.

Two case histories are presented in which near-surface water-bearing formations and their overburden are examined. This survey utilized a combination of traditional geoelectric methods (direct current resistivity and time domain induced polarization) and a special shallow-depth engineering geophysical sounding method. This latter method was developed in Hungary to investigate near-surface unconsolidated formations such as clay, silt, sand, gravel and other similarly “penetratable” formations. For a gravel terrace, in addition to the usual parameter maps (resistivity, thickness, polarizability), combined multiparametric characterization maps have been plotted. These maps illustrate the hydrogeologic value of the water-bearing formations and the protecting capacity of the overburden better than the conventional parameter maps. Surface measurement results together with filtration coefficient values show how an inexpensive geophysical survey can successfully be applied in estimating the dangerous or protected situation of near-surface reservoirs and how such a survey can be used for siting reservoirs. This work enabled the near-surface geological structure to be determined, hereby providing orientation for more expensive, highly detailed surveys.

The aim of this study was to examine the relationship of semen parameters, sexual function-related hormones and waist/hip ratio. Eighty-one selected patients presenting with infertility were examined. Weight, height, waist circumference and hip circumference were measured, and reproduction-related hormone levels were determined. Semen was analysed by conventional methods. Semen volume, sperm concentration, motility, total sperm count, total motile sperm cell number, rapid progressive motile sperm count and reproduction-related hormone levels [follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, 17beta-oestradiol and sexual hormone-binding globulin (SHBG)]. Significant correlations were found: (i) weight, waist circumference and hip circumference versus testosterone level, SHBG level, and testosterone/17beta-oestradiol ratio; (ii) hip circumference versus sperm concentration; (iii) waist circumference and hip circumference versus sperm count, total motile sperm cell number and rapid progressive motile sperm count; (iv) weight versus total sperm count and total motile sperm cell number; (v) waist circumference and hip circumference versus prolactin level (positively) and SHBG (negatively); (vi) waist circumference and waist/hip ratio versus semen volume. It can be concluded that the waist/hip ratio is correlated with the reproductive hormone levels. Although both the waist circumference and hip circumference correlated with the semen characteristics, the waist/hip ratio did not.

A randomized, placebo-controlled clinical pilot study was performed in order to examine the effect of magnesium-orotate in male idiopathic infertility. Ten males were treated daily for 90 consecutive days with 3000 mg magnesium-orotate (Magnerot) tablets (Group M). As a control, ten other males were treated in the same way with placebo (Group P). Conventional microscopic sperm characteristics (sperm concentration, motility ratio, total number of motile sperm cells, normal morphology ratio), plus total and ionized magnesium levels in seminal plasma and blood serum were evaluated both prior to treatment and on day 90, at the conclusion of the study. No significant changes in sperm characteristics, blood ionized or total Mg, or ejaculate total Mg levels were detected. However, ejaculate ionized Mg levels increased in Group M from 0.18 +/- 0.05 to 0.30 +/- 0.05 (mmol/l; mean +/- SD, p0.05). Within the observation period of 3 months, one pregnancy occurred in the partner of a male from Group M. In conclusion, magnesium-orotate treatment at a dose of 3000 mg/day leads neither to a significant improvement of sperm variables nor does it increase the pregnancy rates of female partners of treated males as compared to those of controls. Thus, magnesium-orotate treatment was not shown to be effective therapy for idiopathic male infertility.

The tricyclic core of the martinellines has been synthe- sised stereoselectively in two steps, using 1,3-dipolar cycloaddition of azomethine ylides as a key step.

Aberrant activity of receptor tyrosine kinases (RTKs) has been associated with tumor progression in a wide variety of human malignancies, making them promising drug targets for cancer therapy. Although, in some instances, specific inhibition of just one of these RTKs suffices for inhibition of tumor progression, in the majority of cases, targeting more than one RTK could be required for therapeutic efficacy. Moreover, increased expression or activation of RTKs is often associated with resistance to standard chemotherapy agents or signal transduction modulators. S 49076 is a novel, potent, ATP-competitive tyrosine kinase inhibitor of the RTKs MET, AXL and FGFR. S 49076 blocks autophosphorylation of these RTKs and their downstream signaling in cells with IC50 values of less than 50 nM in the case of MET and AXL, and at below 200 nM for FGFR1/2/3. In vitro, S 49076 inhibits the proliferation of MET- and FGFR2- dependent gastric cancer cells, blocks MET-driven migration of lung carcinoma cells and inhibits colony formation of hepatocarcinoma cells overexpressing FGFR2 and AXL. In vivo, oral administration of S 49076 inhibits MET autophosphorylation and tumor growth in subcutaneous GTL-16 human gastric carcinoma and U87-MG human glioblastoma at 6 mg/kg/day. In FGFR2-dependent SNU-16 gastric tumors S 49076 inhibits FGFR2 autophosphorylation, downstream signaling and tumor growth at 25 mg/kg/day. In a panel of 53 patient-derived tumors and 14 cell lines of diverse origin growing in three-dimensional in vitro culture, twenty-five (37%) were found to be sensitive to S 49076 at 1 µM or less. In the majority of cases, analysis of the expression, activation and mutation status of MET, AXL, FGFR1/2/3 and other target kinases of S 49076 as well as that of major signaling proteins enabled hypotheses to be made concerning the sensitivity or resistance to S 49076. Moreover, in many of these resistant tumors, a rationale for association of S 49076 with other targeted therapies emerged. Examples of the efficacy of such combined therapies will be shown. Based on these preclinical studies showing a favorable and novel pharmacological profile of S 49076, a phase I study is currently underway in patients with advanced solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 848. doi:1538-7445.AM2012-848

Receptor tyrosine kinases (RTKs) are key regulators of a multitude of cell processes, including survival, proliferation, migration, invasion and angiogenesis. Aberrant activity of certain of these receptor tyrosine kinases has been associated with tumor progression in a wide variety of human malignancies, making them promising drug targets for cancer therapy. Although, in some instances, specific inhibition of just one of these RTKs suffices for inhibition of tumor progression, in the majority of cases, targeting more than one RTK could be required for therapeutic efficacy. These RTKs include MET, the receptor for hepatocyte growth factor (HGF), the fibroblast growth factor receptor, FGFR, and AXL. Dysregulation of MET activity, due to its overexpression or mutation, or overexpression of its ligand, has been consistently associated with aggressive phenotype, resistance to certain anti-cancer therapies and poor outcome. The FGFRs have a well-documented role in tumor angiogenesis, and, more recently, have been implicated directly in tumor cell survival, proliferation and metastasis in a wide range of tumor types. AXL is one of a family of three tyrosine kinase receptors (TAM family) involved in the pathogenesis of several human cancers and has also recently incited interest as a cancer therapeutic target. S 49076 is a novel, potent, ATP-competitive tyrosine kinase inhibitor of MET, FGFR1/2/3 and AXL. S 49076 blocks autophosphorylation of these RTKs and their downstream signaling in cells with IC50 values of between 1 and 200 nM depending on the target and cell line. Furthermore, in kinase binding assays, S 49076 also binds to clinically-relevant MET mutated isoforms and a number of other kinases implicated in cancer pathology at concentrations of less than 100 nM. S 49076 is not, however, a potent inhibitor of VEGFR2. Although VEGFR2 is implicated in tumor angiogenesis, it also plays a major physiological role in the maintenance of vascular tone, and its inhibition by other RTK inhibitors has limited dosing of these molecules in the clinic. The unique inhibition profile of S 49076 may allow inhibition of oncogenic RTKs potentially without toxic effects encountered by VEGFR2 inhibitors. In vitro, S 49076 inhibits the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocks MET-driven migration of lung carcinoma cells and inhibits colony formation of AXL-overexpressing hepatocarcinoma cells. In vivo, oral administration of S 49076 inhibits > 80% MET autophosphorylation in subcutaneous GTL-16 human gastric carcinoma tumors at 3 mg/kg. In both this GTL-16 model and in the MET-dependent U87-MG human glioblastoma model, S 49076 inhibits > 80% tumor growth at 6 mg/kg/day. S 49076 also inhibits FGFR2 autophosphorylation, downstream signaling and tumor growth in FGFR2-dependent SNU-16 gastric tumors, and tumor growth in LS-174T colon carcinoma. Based on these preclinical studies showing a favorable and novel pharmacological profile and the potential of S 49076 as innovative anticancer agent, a phase I study is planned soon to evaluate an oral formulation of S 49076 in patients with advanced solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A238.

The intensiv e gro wth of industrial and agricultural activit y causes an increase of polluted areas. In order to predict the spreading of near-surface con tamination it is essen tial to be familiar with the hydrogeological parameters of the investigated earth. The cone penetration technology is capable to resolv e the structure of the subsurface in detail and logs various physical parameters during soil penetration. Cone penetration tests (CPT) were performed at the test site Krauthausen to investigate the aquifer's heterogeneit y in detail. We presen t the results of the CPT surv ey at the test site and the estimated three dimensional heterogeneous distribution of physical soil prop erties. We estimated the hydraulic conductivit y from those data using regression analysis. Therefore the CPT metho d is capable to gain a spatial, highly resolv ed data set of the hydraulic conductivit y distribution. Furthermore we used this data set to estimate the spatial heterogeneit y of hydraulic conductivit y, i.e. the correlation length and anisotrop y within the aquifer.