PAMIHR. A Parallel FORTRAN Program for Multidimensional Quadrature on Distributed Memory Architectures

Abstract. PAMIHR: a parallel adaptive routine for the approximate computation of a multidimensional integral over a hyperrectangular region is described. The software is designed to efficiently run on a MIMD distributed memory environment, and it's based on the widely diffused communication system BLACS. PAMIHR, further, gives special attention to the problems of scalability and of load balancing among the processes

Highly selective toxic and proapoptotic effects of two dimeric ribonucleases on thyroid cancer cells compared to the effects of doxorubicin

The lack of selectivity of conventional antitumour drugs against cancer cells is responsible for their high toxicity. The development of new tumour-specific drugs is therefore highly needed. We tested the cytotoxic effects and the nature of cell death induced by a naturally dimeric bovine RNase and a newly engineered dimeric human RNase upon three genetically well-defined normal and malignant thyroid cell systems. RNases effects were compared with those of doxorubicin, a conventional antineoplastic drug. Our results show significant and selective proapoptotic effects exerted on tumour cells by both RNases, the strength of their cytotoxic and apoptotic activity being directly related to the degree of cell malignancy. No toxic effects were observed upon normal cells. Doxorubicin showed, instead, cytotoxic and apoptotic effects also against normal cells. The in vitro results were corroborated by the antitumour action of both dimeric RNases towards a malignant human thyroid tumour grown in nude mice. These results indicate a selective action of dimeric RNases against cancer cells and suggest the potential application of these molecules or their derivatives to the treatment of aggressive subtypes of thyroid cancer

Mechanism of retinoic acid-induced transcription: histone code, DNA oxidation and formation of chromatin loops

Histone methylation changes and formation of chro- matin loops involving enhancers, promoters and 3′ end regions of genes have been variously associ- ated with active transcription in eukaryotes. We have studied the effect of activation of the retinoic A re- ceptor, at the RARE–promoter chromatin of CASP9 and CYP26A1 genes, 15 and 45 min following RA ex- posure, and we found that histone H3 lysines 4 and 9 are demethylated by the lysine-specific demethylase, LSD1 and by the JMJ-domain containing demethy- lase, D2A. The action of the oxidase (LSD1) and a dioxygenase (JMJD2A) in the presence of Fe++ elic- its an oxidation wave that locally modifies the DNA and recruits the enzymes involved in base and nu- cleotide excision repair (BER and NER). These events are essential for the formation of chromatin loop(s) that juxtapose the RARE element with the 5′ tran- scription start site and the 3′ end of the genes. The RARE bound-receptor governs the 5′ and 3′ end se- lection and directs the productive transcription cycle of RNA polymerase. These data mechanistically link chromatin loops, histone methylation changes and localized DNA repair with transcription

The Challenge of Onboard SAR Processing: A GPU Opportunity

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A human, compact, fully functional anti-ErbB2 antibody as a novel antitumour agent

A new human, compact antibody was engineered by fusion of a human, antitumour ErbB2-directed scFv with a human IgG1 Fc domain. Overexpression of the ErbB2 receptor is related to tumour aggressiveness and poor prognosis. This new immunoagent meets all criteria for a potential anticancer drug: it is human, hence poorly or not immunogenic; it binds selectively and with high affinity to target cells, on which it exerts an effective and selective antiproliferative action, including both antibody-dependent and complement-dependent cytotoxicity; it effectively inhibits tumour growth in vivo. Its compact molecular size should provide for an efficient tissue penetration, yet suitable to a prolonged serum half-life

A novel fully human antitumour immunoRNase targeting ErbB2-positive tumours

BACKGROUND: ErbB2 is an attractive target for immunotherapy, as it is a tyrosine kinase receptor overexpressed on tumour cells of different origin, with a key role in the development of malignancy. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment. METHODS: A novel human immunoRNase, called anti-ErbB2 human compact antibody-RNase (Erb-hcAb-RNase), made up of the compact anti-ErbB2 antibody Erbicin-human-compact Antibody (Erb-hcAb) and human pancreatic RNase (HP-RNase), has been designed, expressed in mammalian cell cultures and purified. The immunoRNase was then characterised as an enzymatic protein, and tested for its biological actions in vitro and in vivo on ErbB2-positive tumour cells. RESULTS: Erb-hcAb-RNase retains the enzymatic activity of HP-RNase and specifically binds to ErbB2-positive cells with an affinity comparable with that of the parental Erb-hcAb. Moreover, this novel immunoRNase is endowed with an effective and selective antiproliferative action for ErbB2-positive tumour cells both in vitro and in vivo. Its antitumour activity is more potent than that of the parental Erb-hcAb as the novel immunoconjugate has acquired RNase-based cytotoxicity in addition to the inhibitory growth effects, antibody-dependent and complement-dependent cytotoxicity of Erb-hcAb. CONCLUSION: Erb-hcAb-RNase could be a promising candidate for the immunotherapy of ErbB2-positive tumours

Low Rates of Both Lipid-Lowering Therapy Use and Achievement of Low-Density Lipoprotein Cholesterol Targets in Individuals at High-Risk for Cardiovascular Disease across Europe

Aims To analyse the treatment and control of dyslipidaemia in patients at high and very high cardiovascular risk being treated for the primary prevention of cardiovascular disease (CVD) in Europe. Methods and Results Data were assessed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov identifier: NCT00882336), which included a randomly sampled population of primary CVD prevention patients from 12 European countries (n = 7641). Patients’ 10-year risk of CVD-related mortality was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm, identifying 5019 patients at high cardiovascular risk (SCORE 5% and/or receiving lipid-lowering therapy), and 2970 patients at very high cardiovascular risk (SCORE 10% or with diabetes mellitus). Among high-risk individuals, 65.3% were receiving lipid-lowering therapy, and 61.3% of treated patients had uncontrolled low-density lipoprotein cholesterol (LDL-C) levels ( 2.5 mmol/L). For very-high-risk patients (uncontrolled LDL-C levels defined as 1.8 mmol/L) these figures were 49.5% and 82.9%, respectively. Excess 10-year risk of CVD-related mortality (according to SCORE) attributable to lack of control of dyslipidaemia was estimated to be 0.72%and 1.61% among high-risk and very-high-risk patients, respectively. Among high-risk individuals with uncontrolled LDL-C levels, only 8.7% were receiving a high-intensity statin (atorvastatin 40 mg/day or rosuvastatin 20 mg/day). Among veryhigh- risk patients, this figure was 8.4%. Conclusions There is a considerable opportunity for improvement in rates of lipid-lowering therapy use and achievement of lipid-level targets in high-risk and very-high-risk patients being treated for primary CVD prevention in EuropeWriting support was provided by Oxford PharmaGenesis Ltd, Oxford, UK, and was funded by AstraZenec

Computing at SuperB

Domenico Del Prete*, Fabrizio Bianchi, Vania Boccia, Vincenzo Ciaschini, Marco Corvo, Guglielmo De Nardo, Andrea Di Simone, Giacinto Donvito, Armando Fella, Paolo Franchini, Francesco Giacomini, Alberto Gianoli, Giuliano Laccetti, Stefano Longo, Steffen Luitz, Eleonora Luppi, Matteo Manzali, Leonardo Merola, Silvio Pardi, Alejandro Perez, Matteo Rama, Guido Russo, Bruno Santeramo, Roberto Stroili, Luca Tommasett