Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

New water soluble, enantiopure arene ruthenium compound SRuSN-(1R, 4S)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (Bn = benzyl, 1a') has been synthesized. The novel compound along with that previously described RRuRN-(1S, 4R)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a' was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a' induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a' towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells

AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer

Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry-based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate-specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high versus AKT1-high tumors, or in normal versus tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our fi ndings show how prostate tumors undergo a metabolic reprogramming that refl ects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.Instituto de Investigaciones Bioquímicas de La PlataFacultad de Ciencias Médica

Relativistic Heavy--Ion Collisions in the Dynamical String--Parton Model

We develop and extend the dynamical string parton model. This model, which is based on the salient features of QCD, uses classical Nambu-Got\=o strings with the endpoints identified as partons, an invariant string breaking model of the hadronization process, and interactions described as quark-quark interactions. In this work, the original model is extended to include a phenomenological quantization of the mass of the strings, an analytical technique for treating the incident nucleons as a distribution of string configurations determined by the experimentally measured structure function, the inclusion of the gluonic content of the nucleon through the introduction of purely gluonic strings, and the use of a hard parton-parton interaction taken from perturbative QCD combined with a phenomenological soft interaction. The limited number of parameters in the model are adjusted to $e^+e^-$ and $p$--$p$ data. Utilizing these parameters, the first calculations of the model for $p$--$A$ and $A$--$A$ collisions are presented and found to be in reasonable agreement with a broad set of data.Comment: 26 pages of text with 23 Postscript figures placed in tex

AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer

Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry-based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate-specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high versus AKT1-high tumors, or in normal versus tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our fi ndings show how prostate tumors undergo a metabolic reprogramming that refl ects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.Instituto de Investigaciones Bioquímicas de La PlataFacultad de Ciencias Médica

Launch of the Space experiment PAMELA

PAMELA is a satellite borne experiment designed to study with great accuracy cosmic rays of galactic, solar, and trapped nature in a wide energy range protons: 80 MeV-700 GeV, electrons 50 MeV-400 GeV). Main objective is the study of the antimatter component: antiprotons (80 MeV-190 GeV), positrons (50 MeV-270 GeV) and search for antimatter with a precision of the order of 10^-8). The experiment, housed on board the Russian Resurs-DK1 satellite, was launched on June, 15, 2006 in a 350*600 km orbit with an inclination of 70 degrees. The detector is composed of a series of scintillator counters arranged at the extremities of a permanent magnet spectrometer to provide charge, Time-of-Flight and rigidity information. Lepton/hadron identification is performed by a Silicon-Tungsten calorimeter and a Neutron detector placed at the bottom of the device. An Anticounter system is used offline to reject false triggers coming from the satellite. In self-trigger mode the Calorimeter, the neutron detector and a shower tail catcher are capable of an independent measure of the lepton component up to 2 TeV. In this work we describe the experiment, its scientific objectives and the performance in the first months after launch.Comment: Accepted for publication on Advances in Space Researc

Impacto da adubação orgânica sobre a incidência de tripes em cebola.

Analisou-se a relação entre adubação orgânica e a incidência de Thrips tabaci Lind. em cebola (Allium cepa L), na EE de Ituporanga,entre agosto e dezembro de 1998. Os tratamentos foram determinados de acordo com a necessidade de N para a cultura pela análise de solo. Empregou-se como fonte orgânica diversos adubos fornecendo 75 Kg/ha de N (esterco suíno; adubo Barriga Verde proveniente de esterco de aves; composto orgânico; esterco de peru; húmus); 37,5 Kg/ha de N (metade da dose normal com esterco de suíno); as testemunhas foram adubação mineral fornecendo 30-120-60 kg/ha de N-P2O5-K2O e o dobro da dose (60-240-120 kg/ha de N-P2O5-K2O); e testemunha sem adubação. Nenhum tratamento apresentou incidência de T. tabaci superior à testemunha sem adubo. A adubação mineral em relação à orgânica não favoreceu significativamente a incidência de T. tabaci . O processo de conversão do manejo do solo da área experimental de convencional para orgânico pode ter favorecido a infestação similar do inseto entre tratamentos. No período de maior incidência de T. tabaci, a relação com nutrientes foi descrita por um modelo envolvendo K/Zn, B e N de maneira positiva. A correlação entre nutrientes e T. tabaci não foi linear na maioria das avaliações. A adubação orgânica pode substituir a adubação mineral na cultura da cebola, pois foi possível atingir níveis de produtividade similares para ambos tratamentos

PAMELA - A Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics

The PAMELA experiment is a satellite-borne apparatus designed to study charged particles in the cosmic radiation with a particular focus on antiparticles. PAMELA is mounted on the Resurs DK1 satellite that was launched from the Baikonur cosmodrome on June 15th 2006. The PAMELA apparatus comprises a time-of-flight system, a magnetic spectrometer, a silicon-tungsten electromagnetic calorimeter, an anticoincidence system, a shower tail catcher scintillator and a neutron detector. The combination of these devices allows antiparticles to be reliably identified from a large background of other charged particles. This paper reviews the design, space qualification and on-ground performance of PAMELA. The in-orbit performance will be discussed in future publications.The PAMELA experiment is a satellite-borne apparatus designed to study charged particles in the cosmic radiation with a particular focus on antiparticles. PAMELA is mounted on the Resurs DK1 satellite that was launched from the Baikonur cosmodrome on June 15th 2006. The PAMELA apparatus comprises a time-of-flight system, a magnetic spectrometer, a silicon-tungsten electromagnetic calorimeter, an anticoincidence system, a shower tail catcher scintillator and a neutron detector. The combination of these devices allows antiparticles to be reliably identified from a large background of other charged particles. This paper reviews the design, space qualification and on-ground performance of PAMELA. The in-orbit performance will be discussed in future publications

The Movember Global Action Plan 1 (GAP1): Unique Prostate Cancer Tissue Microarray Resource

BackgroundThe need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations.MethodsThree separate TMA sets were built that differ by purpose and disease state.ResultsThe intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases.ConclusionsThe GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation.ImpactThis resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.</p