Prevention of fraud, corruption and bribery committed through legal entities for the purpose of financial and economic gain

In Dutch law there is no overall criminal offence on corruption. In Dutch criminal law corruption is divided in specific criminal offences which all have their own specific definition. Most corruption can be qualified as a criminal offence but it is sometimes difficult to qualify them as such. Qualifying in general as an offence is easy (forgery for example) but proving that the act specifically qualifies as corruption is harder. Given this general observation, a specific form of active corruption in the Dutch Criminal Code (DCC) seems relevant regarding to art. 2, par. 1, section a of the Framework Decision 2003/568/JHA of 22 July 2003 on combatting corruption in the private sector. Art. 328ter par. 2 of the DCC deals with bribery of a private person: punishable is the private person that gives or offers someone other than a civil servant, working in employement or acting as an agent, in exchange for something he has done or not done or will do or refrain from doing in the performance of his burden, a gift or promise, or a service of that nature or under such circumstances that he should reasonable assume that such a gift or promise will be withheld from his employer or principal contrary to good faith. This provision covers active corruption on the initiative of all private persons, including employees, managers and directors of private entities. However, this provision is limited to the bribery of employees and managers and seems to exclude the bribery of a director of a private entity. This means that this provision does not fully cover the obligation under art. 2, par. 1, section a of the Framework Decision 2003/568/JHA. In addition to art. 328ter DCC more general provisions can be used, especcially when the active corruption involves bribery of a director of a private entity. Dependant upon the circumstances of the case the provisions on forgery, falsifying of documents and cheating could be relevant. These circumstances should then involve: the forgery of a written statement with the intention to use this statement as genuine (art. 225 DCC), the falsification of stock certificates or other official certificates or documents, (art. 226 DCC) or the elements of cheating. In art. 326 of the DCC cheating is described as: the person who intentionally favours himself or another person in a unlawfull way, by using a false name, a false capacity, cunning manouvres or fabrications, moving another person to hand over a good, a service, information or a debt

Lineshape of the Lambda(1405) Hyperon Measured Through its Sigma0 pion0 Decay

The pp -> p K+ Y0 reaction has been studied for hyperon masses m(Y0)<1540 MeV/c2 at COSY-Juelich by using a 3.65 GeV/c circulating proton beam incident on an internal hydrogen target. Final states comprising two protons, one positively charged kaon and one negatively charged pion have been identified with the ANKE spectrometer. Such configurations are sensitive to the production of the ground state Lambda and Sigma0 hyperons as well as the Sigma0(1385) and Lambda(1405) resonances. Applying invariant- and missing-mass techniques, the two overlapping excited states could be well separated, though with limited statistics. The shape and position of the Lambda(1405) distribution, reconstructed cleanly in the Sigma0 pion0 channel, are similar to those found from other decay modes and there is no obvious mass shift. This finding constitutes a challenging test for models that predict Lambda(1405) to be a two-state resonance.Comment: 10 pages, 4 figures, accepted for publication in Phys. Lett.

Two Multiplex Assays That Simultaneously Identify 22 Possible Mutation Sites in the KRAS, BRAF, NRAS and PIK3CA Genes

Recently a number of randomized trials have shown that patients with advanced colorectal cancer do not benefit from therapies targeting the epidermal growth factor receptor when their tumors harbor mutations in the KRAS, BRAF and PIK3CA genes. We developed two multiplex assays that simultaneously screen 22 nucleotides in the KRAS, NRAS, BRAF and PIK3CA genes for mutations. The assays were validated on 294 tumor DNA samples from patients with advanced colorectal cancer. In these samples 119 KRAS codon 12 and 13 mutations had been identified by sequence analysis, 126 tumors were wild-type for KRAS and the analysis failed in 49 of the 294 samples due to poor DNA quality. The two mutation assays detected 130 KRAS mutations, among which were 3 codon 61 mutations, and in addition 32 PIK3CA, 13 BRAF and 6 NRAS mutations. In 19 tumors a KRAS mutation was found together with a mutation in the PIK3CA gene. One tumor was mutant for both PIK3CA and BRAF. In summary, the mutations assays identified 161 tumors with a mutation, 120 were wild-type and the analysis failed in 13. The material cost of the 2 mutation assays was calculated to be 8-fold lower than the cost of sequencing required to obtain the same data. In addition, the mutation assays are less labor intensive. We conclude that the performance of the two multiplex mutation assays was superior to direct sequencing. In addition, these assays are cheaper and easier to interpret. The assays may also be of use for selection of patients with other tumor types

S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer

Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK

Oxidative functionalization mechanisms in organic synthesis using fenton reaction systems

We argued an oxywater-oxene concept for hydrogen peroxide transformation in Fenton reaction systems and used this interpretation for mechanisms explanation of hydroperoxide monooxygen oxidative functionalization processes (alkane and arene hydroxylation, alkene epoxidation, Baeyer-Villiger ketone oxidation to ester, organonitrogen compounds N-oxidation and organosulfur compounds S-oxidation) and dioxygen alkene and alkadiene functionalization processes (synthesis of hydroperoxides and cyclic peroxides)

Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma

Using tissue microarrays (TMAs) we studied COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on clinicopathological correlations and the outcome of patients with malignant melanoma (MM). TMA-1 contained normal and tumor tissues (n = 3448) from 47 organs including skin neoplasms (n = 323); TMA-2 88 primary MM, 101 metastases, and 161 benign nevi. Based on a biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy metastases of 36 patients participating in a randomized trial with metastatic (stage IV) melanoma were investigated using TMA-3. COX2/PPARG immunoreactivity significantly increased from nevi to primary MM and metastases; COX2 positivity was associated with advanced Clark levels and shorter recurrence-free survival. Patients with PPARG-positive metastases and biomodulatory metronomic chemotherapy alone or combined with COX2/PPARG-targeting showed a significantly prolonged progression-free survival. Regarding primary MM, COX2 expression indicates an increased risk of tumor recurrence. In metastatic MM, PPARG expression may be a predicitive marker for response to biomodulatory stroma-targeted therapy

Production of the 1S0 diproton in the pp -> pp pi0 reaction at 0.8 GeV

The pp -> pp pi0 differential cross section has been measured with the ANKE spectrometer at COSY-Juelich for pion cms angles between 0 and 15.4 degrees at a proton beam energy of 0.8 GeV. The selection of diproton pairs with an excitation energy E_{pp} < 3 MeV ensures that the final pp system is dominantly in the spin-singlet 1S0 state. The kinematics are therefore very similar to those of pp -> d pi+ but with different spin and isospin transitions. The results will thus provide a crucial extra test of pion production models in nucleon-nucleon collisions. The cross sections, which are over two orders of magnitude smaller than those of pp -> d pi+, show a forward dip, even stronger than that seen at lower energies. This behaviour is well reproduced in a theoretical model that includes P-wave Delta-N states.Comment: 10 pages, 5 eps figures, prepared using elsart.cl

Long term geological record of a global deep subsurface microbial habitat in sand injection complexes

Peer reviewedPublisher PD

Role of Fibroblast Growth Factors in the Crosstalk of Hepatic Stellate Cells and Uveal Melanoma Cells in the Liver Metastatic Niche

Hepatic metastasis is the critical factor determining tumor-associated mortality in different types of cancer. This is particularly true for uveal melanoma (UM), which almost exclusively metastasizes to the liver. Hepatic stellate cells (HSCs) are the precursors of tumor-associated fibroblasts and support the growth of metastases. However, the underlying mechanisms are widely unknown. Fibroblast growth factor (FGF) signaling is dysregulated in many types of cancer. The aim of this study was to analyze the pro-tumorigenic effects of HSCs on UM cells and the role of FGFs in this crosstalk. Conditioned medium (CM) from activated human HSCs significantly induced proliferation together with enhanced ERK and JNK activation in UM cells. An in silico database analysis revealed that there are almost no mutations of FGF receptors (FGFR) in UM. However, a high FGFR expression was found to be associated with poor survival for UM patients. In vitro, the pro-tumorigenic effects of HSC-CM on UM cells were abrogated by a pharmacological inhibitor (BGJ398) of FGFR1/2/3. The expression analysis revealed that the majority of paracrine FGFs are expressed by HSCs, but not by UM cells, including FGF9. Furthermore, the immunofluorescence analysis indicated HSCs as a cellular source of FGF9 in hepatic metastases of UM patients. Treatment with recombinant FGF9 significantly enhanced the proliferation of UM cells, and this effect was efficiently blocked by the FGFR1/2/3 inhibitor BGJ398. Our study indicates that FGF9 released by HSCs promotes the tumorigenicity of UM cells, and thus suggests FGF9 as a promising therapeutic target in hepatic metastasis