Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study

Hepatoblastoma (HB) is a rare malignant liver tumour found in infants. Many heterogenous histological tumour subtypes exist. Although survival rates have improved dramatically in recent years with the use of platinum-based chemotherapy, there still exists a subset of HB that does not respond to treatment. There are currently no tumour biomarkers in use and in this study we aim to evaluate potential biomarkers to aid identification of relapse cases that would otherwise be overlooked by current prognostication. This may identify patients that would benefit from more aggressive therapy and could improve overall survival rates. We used immunohistochemistry to analyse the expression of β-catenin, E-cadherin, Cyclin D1, Ki-67 and alpha-fetoprotein (AFP) protein in tumours from 91 patients prospectively enroled into the SIOPEL 3 clinical trial. The relationship between these biomarkers and clinicopathologic features and patient survival were statistically analysed. We identified one biomarker, Cyclin D1, which has a correlation with mixed epithelial/mesenchymal HB approaching significance (P=0.07). Survival analysis using these markers has revealed two potential prognostic indicators; Cyclin D1 and Ki-67 (P=0.01, 0.01).

Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of survival and clinical response in women with ovarian cancer

Background. The mTOR pathway is commonly altered in human tumors and promotes cell survival and proliferation. Preliminary evidence suggests this pathway's involvement in chemoresistance to platinum and taxanes, first line therapy for epithelial ovarian cancer. A pathway-based approach was used to identify individual germline single nucleotide polymorphisms (SNPs) and cumulative effects of multiple genetic variants in mTOR pathway genes and their association with clinical outcome in women with ovarian cancer. ^ Methods. The case-series was restricted to 319 non-Hispanic white women with high grade ovarian cancer treated with surgery and platinum-based chemotherapy. 135 SNPs in 20 representative genes in the mTOR pathway were genotyped. Hazard ratios (HRs) for death and Odds ratios (ORs) for failure to respond to primary therapy were estimated for each SNP using the multivariate Cox proportional hazards model and multivariate logistic regression model, respectively, while adjusting for age, stage, histology and treatment sequence. A survival tree analysis of SNPs with a statistically significant association (p<0.05) was performed to identify higher order gene-gene interactions and their association with overall survival. ^ Results. There was no statistically significant difference in survival by tumor histology or treatment regimen. The median survival for the cohort was 48.3 months. Seven SNPs were significantly associated with decreased survival. Compared to those with no unfavorable genotypes, the HR for death increased significantly with the increasing number of unfavorable genotypes and women in the highest risk category had HR of 4.06 (95% CI 2.29–7.21). The survival tree analysis also identified patients with different survival patterns based on their genetic profiles. 13 SNPs on five different genes were found to be significantly associated with a treatment response, defined as no evidence of disease after completion of primary therapy. Rare homozygous genotype of SNP rs6973428 showed a 5.5-fold increased risk compared to the wild type carrying genotypes. In the cumulative effect analysis, the highest risk group (individuals with ≥8 unfavorable genotypes) was significantly less likely to respond to chemotherapy (OR=8.40, 95% CI 3.10–22.75) compared to the low risk group (≤4 unfavorable genotypes). ^ Conclusions. A pathway-based approach can demonstrate cumulative effects of multiple genetic variants on clinical response to chemotherapy and survival. Therapy targeting the mTOR pathway may modify outcome in select patients.^

Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A

Protein kinase A type I plays a key role in neoplastic transformation, conveying mitogenic signals of different growth factors and oncogenes. Inhibition of protein kinase A type I by antisense oligonucleotides targeting its RIα regulatory subunit results in cancer cell growth inhibition in vitro and in vivo. A novel mixed backbone oligonucleotide HYB 190 and its mismatched control HYB 239 were tested on soft agar growth of several human cancer cell types. HYB 190 demonstrated a dose-dependent inhibition of colony formation in all cell lines whereas the HYB 239 at the same doses caused a modest or no growth inhibition. A noninhibitory dose of each mixed backbone oligonucleotide was used in OVCAR-3 ovarian and GEO colon cancer cells to study whether any cooperative effect may occur between the antisense and a series of cytotoxic drugs acting by different mechanisms. Treatment with HYB 190 resulted in an additive growth inhibitory effect with several cytotoxic drugs when measured by soft agar colony formation. A synergistic growth inhibition, which correlated with increased apoptosis, was observed when HYB 190 was added to cancer cells treated with taxanes, platinum-based compounds, and topoisomerase II selective drugs. This synergistic effect was also observed in breast cancer cells and was obtained with other related drugs such as docetaxel and carboplatin. Combination of HYB 190 and paclitaxel resulted in an accumulation of cells in late S-G2 phases of cell cycle and marked induction of apoptosis. A cooperative effect of HYB 190 and paclitaxel was also obtained in vivo in nude mice bearing human GEO colon cancer xenografts. These results are the first report of a cooperative growth inhibitory effect obtained in a variety of human cancer cell lines by antisense mixed backbone oligonucleotide targeting protein kinase A type I-mediated mitogenic signals and specific cytotoxic drugs.

Refinery Nonconventional Feedstocks: Influence of the Coprocessing of Vacuum Gas Oil and Low Density Polyethylene in Fluid Catalytic Cracking Unit on Full Range Gasoline Composition

Gasoline coming from refinery fluid catalytic cracking (FCC) unit is a major contributor to the total commercial grade gasoline pool. The contents of the FCC gasoline are primarily paraffins, naphthenes, olefins, aromatics, and undesirables such as sulfur and sulfur containing compounds in low quantities. The proportions of these components in the FCC gasoline invariable determine its quality as well as the performance of the associated downstream units. The increasing demand for cleaner and lighter fuels significantly influences the need not only for novel processing technologies but also for alternative refinery and petrochemical feedstocks. Current and future clean gasoline requirements include increased isoparaffins contents, reduced olefin contents, reduced aromatics, reduced benzene, and reduced sulfur contents. The present study is aimed at investigating the effect of processing an unconventional refinery feedstock, composed of blend of vacuum gas oil (VGO) and low density polyethylene (LDPE) on FCC full range gasoline yields and compositional spectrum including its paraffins, isoparaffins, olefins, napthenes, and aromatics contents distribution within a range of operating variables of temperature (500–700 °C) and catalyst-feed oil ratio (CFR 5–10) using spent equilibrium FCC Y-zeolite based catalyst in a FCC pilot plant operated at the University of Alicante’s Research Institute of Chemical Process Engineering (RICPE). The coprocessing of the oil-polymer blend led to the production of gasoline with very similar yields and compositions as those obtained from the base oil, albeit, in some cases, the contribution of the feed polymer content as well as the processing variables on the gasoline compositional spectrum were appreciated. Carbon content analysis showed a higher fraction of the C9–C12 compounds at all catalyst rates employed and for both feedstocks. The gasoline’s paraffinicity, olefinicity, and degrees of branching of the paraffins and olefins were also affected in various degrees by the scale of operating severity. In the majority of the cases, the gasoline aromatics tended toward the decrease as the reactor temperature was increased. While the paraffins and iso-paraffins gasoline contents were relatively stable at around 5 % wt, the olefin contents on the other hand generally increased with increase in the FCC reactor temperature.

Ni-CeO2/C Catalysts with Enhanced OSC for the WGS Reaction

In this work, the WGS performance of a conventional Ni/CeO2 bulk catalyst is compared to that of a carbon-supported Ni-CeO2 catalyst. The carbon-supported sample resulted to be much more active than the bulk one. The higher activity of the Ni-CeO2/C catalyst is associated to its oxygen storage capacity, a parameter that strongly influences the WGS behavior. The stability of the carbon-supported catalyst under realistic operation conditions is also a subject of this paper. In summary, our study represents an approach towards a new generation of Ni-ceria based catalyst for the pure hydrogen production via WGS. The dispersion of ceria nanoparticles on an activated carbon support drives to improved catalytic skills with a considerable reduction of the amount of ceria in the catalyst formulation.

Structured carbons as supports for hydrogenation hybrid catalysts prepared by the immobilization of a Rh diamine complex

A CNF-monolith sample (carbon nanofibres grown on a ceramic monolith), and a granular carbon xerogel have been used as supports for hybrid catalysts where the active species is an Rh diamine complex. The advantages of these supports are their open porous structure and their morphology, which make catalyst handling easier and avoid difficult separation processes. The obtained catalysts are noticeably more active than the homogeneous Rh complex and are stable against leaching. At first use, partial reduction of the Rh complex takes place and nanometer-sized Rh particles develop, which increases the catalyst activity. Despite the open porous structure, mass transport limitations are present, especially in the case of the carbon xerogel based catalyst. Differences in internal mass transfer limitations are essentially due to the different diffusional path lengths.

(Bio)funcionalização de superfícies nanoestruturadas para eletrocatálise e desenvolvimento de biossensores eletroquímicos e óticos

Tese de doutoramento, Química (Química Física), Universidade de Lisboa, Faculdade de Ciências, 2016

Ototoxicidade

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Coke formation in the oxidative dehydrogenation of ethylbenzene to styrene by TEOM

A packed bed microbalance reactor setup (TEOM-GC) is used to investigate the formation of coke as a function of time-on-stream on γ-Al2O3 and 3P/SiO2 catalyst samples under different conditions for the ODH reaction of ethylbenzene to styrene. All samples show a linear correlation of the styrene selectivity and yield with the initial coverage of coke. The COX production increases with the coverage of coke. On the 3 wt% P/SiO2 sample, the initial coke build-up is slow and the coke deposition rate increases with time. On alumina-based catalyst samples, a fast initial coke build-up takes place, decreasing with time-on-stream, but the amount of coke does not stabilize. A higher O2 : EB feed ratio results in more coke, and a higher temperature results in less coke. This coking behaviour of Al2O3 can be described by existing "monolayer-multilayer" models. Further, the coverage of coke on the catalyst varies with the position in the bed. For maximal styrene selectivity, the optimal coverage of coke should be sufficient to convert all O2, but as low as possible to prevent selectivity loss by COX production. This is in favour of high temperature and low O2 : EB feed ratios. The optimal coke coverage depends in a complex way on all the parameters: temperature, the O2 : EB feed ratio, reactant concentrations, and the type of starting material. This journal is

Transport in the blood of an anti-tumor water-soluble rutheniun cyclopentadienyl complex: a fluorescence study on albumin binding

Dissertação de mestrado, Qualidade em Análises, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2014

Nuovi processi catalitici per la produzione di syngas

The study of the combined Steam/Dry Reforming (S/DR) process for the production of syngas (CO + H2) from clean biogas was carried out using Ni/Ir bimetallic catalysts on Mg and Al mixed-oxides, obtained by calcination of hydrotalcite-type precursors (Ht) prepared by co-precipitation. The presence of small amounts of Ir promoted the catalytic activity and limited the deactivation phenomena through the formation of a bimetallic alloy, which does the catalyst very active even at lowest temperature and in lack of steam. By integrating a High Temperature–WGS unit (HTS) after the S/DR reactor it was possible to increase the H2 yield of the process. The performance of the Zn/Al/Cu-based catalyst was improved using a templating agent during the synthesis of the catalyst, which increased the catalyst’s structural properties and activity especially at lowest temperatures and at highest contact times. Finally, starting from the laboratory data, it was possible to simulate the S/DR process on industrial scale, evaluating its scalability and environmental impact. The results showed that, using the S/DR technology instead of the current processes, it was possible to reduce the energy costs and the atmospheric emissions of the plant.

Inhibition and characterization of two-metal ion enzymes to treat cancer: dna polymerase Ƞ and topoisomerase II α

Chemotherapeutic drugs can in many ways disrupt the replication machinery triggering apoptosis in cancer cells: some act directly on DNA and others block the enzymes involved in preparing DNA for replication. Cisplatin-based drugs are common as first-line cancer chemotherapics. Another example is etoposide, a molecule that blocks topoisomerase II α leading to the inhibition of dsDNA replication. Despite their efficacy, cancer cells can respond to these treatments over time by overtaking their effects, leading to drug resistance. Chemoresistance events can be triggered by the action of enzymes like DNA polymerase ƞ (Pol η). This polymerase helps also to bypass drug-induced damage in cancer cells, allowing DNA replication and cancer cells proliferation even when cisplatin-based chemotherapeutic drugs are in use. Pol ƞ is a promising drug discovery target, whose inhibition would help in overcoming of drug resistance. This study aims to identify a potent and selective Pol ƞ inhibitor able to improve the efficacy of platinum-based chemotherapeutic drugs. We report the discovery of compound 64 (ARN24964), after an extensive SAR reporting 35 analogs. We evaluated compound 64 on four different cell lines. Interestingly, the molecule is a Pol η inhibitor able to act synergistically with cisplatin. Moreover, we also synthesized a prodrug form that allowed us to improve its stability and the bioavailability. This compound represents an advanced scaffold featuring good potency and DMPK properties. In addition to this central theme, this thesis also describes our efforts in developing and characterize a novel hybrid inhibitor/poison for the human topoisomerase II α enzyme. In particular, we performed specific assays to study the inhibiton of Topoisomesare II α and we evaluated compounds effect on three cancer cell lines. These studies allowed us to identify a compound that is able to inhibit the enzyme with a good pK and a good potency.

Study of Pt/MCM-22 based catalysts in the transformation of n-hexane: effect of rare earth elements and mode of platinum introduction

The bifunctional transformation of n-hexane was carried out over Pt/MCM-22 based catalysts. MCM-22 was synthesized and submitted to ion exchange with rare earth nitrate solutions of La, Nd and Yb, followed by Pt introduction. Three different methods were used to introduce about 1 wt% of Pt in the zeolite: ion exchange, incipient wetness impregnation and mechanical mixture with Pt/Al(2)O(3). The bifunctional catalysts were characterized by transmission electron microscopy and by the model reaction of toluene hydrogenation. These experiments showed that, in the ion exchanged sample, Pt is located both within the inner micropores and on the outer surface, whereas in the impregnated one, the metal is essentially located on the outer surface under the form of large particles. The presence of RE elements increases the hydrogenating activity of Pt/MCM-22 since the location of these species at the vicinity of metal particles causes modification on its electronic properties. Whatever the mode of Pt introduction, a fast initial decrease in conversion is observed for n-hexane transformation, followed by a plateau related to the occurrence of the catalytic transformations at the hemicages located at the outer surface of the crystals. The effect of rare earth elements on the hydrogenating function leads to a lower selectivity in dibranched isomers and increased amounts of light products.

Ultra-thin porous silica coated silver-platinum alloy nano-particle as a new catalyst precursor

Templated sol-gel encapsulation of surfactant-stabilised micelles containing metal precursor(s) with ultra-thin porous silica coating allows solvent extraction of organic based stabiliser from the composites in colloidal state hence a new method of preparing supported alloy catalysts using the inorganic silica-stabilised nano-sized, homogenously mixed, silver - platinum (Ag-Pt) colloidal particles is reported.

Effects of acidic treatments on the pore and surface properties of Ni catalyst supported on activated carbon

Activated carbon as catalyst support was treated with HCl, HNO3, and HF and the effects of acid treatments on the properties of the activated carbon support were studied by N-2 adsorption, mass titration, temperature-programmed desorption (TPD), and X-ray photoelectron spectrometry (XPS). Ni catalysts supported on untreated and treated activated carbons were prepared, characterized and tested for the reforming reaction of methane with carbon dioxide. It is found that acid treatment significantly changed the surface chemical properties and pore structure of the activated carbon. The surface area and pore volume of the carbon supports are generally enhanced upon acid treatment due to the removal of impurities present in the carbon. The adsorption capacity of Ni2+ on the carbon supports is also increased, and the increase can be closely correlated with the surface acidity. The impregnation of nickel salts decreases the surface area and pore volume of carbon supports both in micropores and mesopores. Acid treatment results in a more homogeneous distribution of the nickel salt in carbon. When the impregnated carbons are heated in inert atmosphere, there exists a redox reaction between nickel oxide and the carbon. Catalytic activity tests for methane reforming with carbon dioxide show that the activity of nickel catalysts based on the acid-treated carbon supports is closely related with the surface characteristics of catalysts. (C) 1998 Elsevier Science Ltd. All rights reserved.