A prospective, randomized, open label, phase iii clinical trial of novottf-100a vs best standard of care chemotherapy in patients with recurrent glioblastoma

BACKGROUND: Glioblastoma, the most common adult primary malignant brain tumor, confers poor prognosis (median survival of 15 months) notwithstanding aggressive treatment. Combination chemotherapy including carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used, but has been associated with dose-limiting hematopoietic toxicity. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed glioblastoma patients in an attempt to chemoprotect bone marrowduring combination O6BG/TMZ therapy. METHODS: Three patients have been enrolled in the first cohort. Patients underwent standard radiation therapy without TMZ followed by G-CSF mobilization, apheresis, and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Posttransplant, patients were treated with 28-day cycles of single doseTMZ (472 mg/m2) with 48-hour intravenous O6BG (120 mg/m2 bolus, then 30 mg/m2/d). RESULTS: The BCNU dose was nonmyeloablative with ANC ,500/mL for ≤3 d and nadir thrombocytopenia of 28,000/mL. Gene marking in pre-infusion colony forming units (CFUs) was 70.6%, 79.0%, and 74.0% in Patients 1, 2, and 3, respectively, by CFU-PCR. Following engraftment, gene marking in white blood cells and sorted granulocytes ranged between 0.37-0.84 and 0.33-0.83 provirus copies, respectively, by real-time PCR. Posttransplant gene marking in CFUs from CD34-selected cells ranged from 28.5% to 47.4%. Patients have received 4, 3, and 2 cycles of O6BG/TMZ, respectively, with evidence for selection of gene-modified cells. One patient has received a single dose-escalated cycle at 590 mg/m2 TMZ. No additional extra-hematopoietic toxicity has been observed thus far and all three patients exhibit stable disease at 7-8 months since diagnosis CONCLUSIONS: We believe that these data demonstrate the feasibility of achieving significant engraftment of MGMTP140K-modified cells with a well-tolerated dose of BCNU. Further follow-up will determine whether this approach will allow for further dose escalation of TMZ and improved survival.

Ostéogénèse atypique après séquestrectomies multiples pour fracture ouverte infectée du fémur: un cas [Atypical osteogenesis following multiple sequestrectomies for infected open fracture of the femur: a case]

The authors present the case of an open fracture of femur Cauchoix type II with an infection due to Escherichia coli, Clostridium perfringens, Enterococcus and Aspergillus fumigatus. After several sequestrectomies and five hyperbaric sessions, apyrexia was attained at the end of the third month, the femur having been stabilised with an external fixator. The 15 cm gap due to loss of bone substance, filled at each dressing with an antiseptic iodine based ointment, closed itself finishing as continuous bone five months after the accident, the granulation tissue having been recovered by thin skin grafts. A repeated fracture occurring forty-eight hours after the removal of the Hoffmann frame was treated by fitting an Ilizarov fixator arriving at consolidation in seven months. The authors examine different possibilities of accelerating osteogenesis and highlight the potential role of iodine ointment as inductive to osteogenesis stemming from a periosteal layer seemingly held in place.

Modificació d'un sistema de generació de grafisme per televisió amb la incorporació d'objectes generats amb OpenGL

Els objectius inicials d'aquest projecte eren la incorporació d'OpenGL a l'eina ja existent de generació de grafisme per televisió. Com que l'aplicador ja dissenyat es basava en un reduït tipus d'objectes sobre els quals es podien aplicar diferents paràmetres i agrupar-los de diferents maneres, calia trobar un nou tipus d'objecte que tingués alguna particularitat que el fes prou atractiu per a incorporar-lo a l'aplicació. El resultat va ser un objecte polièdric per a poder-hi mapar diferents textures i un text aplicant-hi una ombra en tres dimensions segons la posició del dibuix.

Herramientas open source para la creación de portales

En aquest treball es proposa una aproximació al món del codi font obert des del punt de vista de la realització de portals col·laboratius i les seves eines involucrades. Per fer-ho, es passa revista als diferents tipus d'aplicacions, plataformes i utilitats que trobem disponibles, i s'agrupen en diferents categories: infraestructura i sistemes, serveis de comunicació, serveis de comunitat, serveis genèrics de portal, eines d'interacció amb sistemes mòbils, eines per al desenvolupament i prova i llibreries de suport.

A Rapid Mapping Study of Smoking Projects and Services Targeted at People Living on Low Income and/or Minority Ethnic Groups

This is a study concerned with community based services aimed at smokers living on a low income and/or black and minority ethnic groups.

Health Inequalities Intervention Tool for Spearheads 2009 (Click SAVE NOT OPEN when prompted)

The Spearhead Intervention Tool has been commissioned by the Department of Health through the Association of Public Health Observatories (APHO). This version of the tool has been updated with latest data for 2005-07. The tool is designed to assist commissioners in Spearhead Primary Care Trusts (PCTs) with their Local Delivery Planning (LDP) and commissioning and to assist Spearhead Local Authorities (LAs) with the delivery of Local Area Agreements (LAAs). It highlights key issues for Spearhead PCTs and LAs to consider in order to achieve the life expectancy element of the Government̢?Ts Public Service Agreement (PSA) on health inequalities by 2010.

Mapping health inequalities across London

Analysis of infant mortality and life expectancy across London by various dimensions of inequality- socioeconomic; gender; geographical, and trends

Re-mapping the molecular features of the human immunodeficiency virus type 1 and human T-cell lymphotropic virus type 1 Brazilian sequences using a bioinformatics unit established in Salvador, Bahia, Brazil, to give support to the viral epidemiology studies

The analysis of genetic data for human immunodeficiency virus type 1 (HIV-1) and human T-cell lymphotropic virus type 1 (HTLV-1) is essential to improve treatment and public health strategies as well as to select strains for vaccine programs. However, the analysis of large quantities of genetic data requires collaborative efforts in bioinformatics, computer biology, molecular biology, evolution, and medical science. The objective of this study was to review and improve the molecular epidemiology of HIV-1 and HTLV-1 viruses isolated in Brazil using bioinformatic tools available in the Laboratório Avançado de Sáude Pública (Lasp) bioinformatics unit. The analysis of HIV-1 isolates confirmed a heterogeneous distribution of the viral genotypes circulating in the country. The Brazilian HIV-1 epidemic is characterized by the presence of multiple subtypes (B, F1, C) and B/F1 recombinant virus while, on the other hand, most of the HTLV-1 sequences were classified as Transcontinental subgroup of the Cosmopolitan subtype. Despite the high variation among HIV-1 subtypes, protein glycosylation and phosphorylation domains were conserved in the pol, gag, and env genes of the Brazilian HIV-1 strains suggesting constraints in the HIV-1 evolution process. As expected, the functional protein sites were highly conservative in the HTLV-1 env gene sequences. Furthermore, the presence of these functional sites in HIV-1 and HTLV-1 strains could help in the development of vaccines that pre-empt the viral escape process.

Functionalization of microstructured open-porous bioceramic scaffolds with human fetal bone cells.

Bone substitute materials allowing trans-scaffold migration and in-scaffold survival of human bone-derived cells are mandatory for development of cell-engineered permanent implants to repair bone defects. In this study, we evaluated the influence on human bone-derived cells of the material composition and microstructure of foam scaffolds of calcium aluminate. The scaffolds were prepared using a direct foaming method allowing wide-range tailoring of the microstructure for pore size and pore openings. Human fetal osteoblasts (osteo-progenitors) attached to the scaffolds, migrated across the entire bioceramic depending on the scaffold pore size, colonized, and survived in the porous material for at least 6 weeks. The long-term biocompatibility of the scaffold material for human bone-derived cells was evidenced by in-scaffold determination of cell metabolic activity using a modified MTT assay, a repeated WST-1 assay, and scanning electron microscopy. Finally, we demonstrated that the osteo-progenitors can be covalently bound to the scaffolds using biocompatible click chemistry, thus enhancing the rapid adhesion of the cells to the scaffolds. Therefore, the different microstructures of the foams influenced the migratory potential of the cells, but not cell viability. Scaffolds allow covalent biocompatible chemical binding of the cells to the materials, either localized or widespread integration of the scaffolds for cell-engineered implants.

Inter- and intrahemispheric dissociations in ideomotor apraxia: a large-scale lesion-symptom mapping study in subacute brain-damaged patients.

Pantomimes of object use require accurate representations of movements and a selection of the most task-relevant gestures. Prominent models of praxis, corroborated by functional neuroimaging studies, predict a critical role for left parietal cortices in pantomime and advance that these areas store representations of tool use. In contrast, lesion data points to the involvement of left inferior frontal areas, suggesting that defective selection of movement features is the cause of pantomime errors. We conducted a large-scale voxel-based lesion-symptom mapping analyses with configural/spatial (CS) and body-part-as-object (BPO) pantomime errors of 150 left and right brain-damaged patients. Our results confirm the left hemisphere dominance in pantomime. Both types of error were associated with damage to left inferior frontal regions in tumor and stroke patients. While CS pantomime errors were associated with left temporoparietal lesions in both stroke and tumor patients, these errors appeared less associated with parietal areas in stroke than in tumor patients and less associated with temporal in tumor than stroke patients. BPO errors were associated with left inferior frontal lesions in both tumor and stroke patients. Collectively, our results reveal a left intrahemispheric dissociation for various aspects of pantomime, but with an unspecific role for inferior frontal regions.

Multiple adenosine 3',5'-cyclic [corrected] monophosphate response element DNA-binding proteins generated by gene diversification and alternative exon splicing.

The protein sequence deduced from the open reading frame of a human placental cDNA encoding a cAMP-responsive enhancer (CRE)-binding protein (CREB-327) has structural features characteristic of several other transcriptional transactivator proteins including jun, fos, C/EBP, myc, and CRE-BP1. Results of Southwestern analysis of nuclear extracts from several different cell lines show that there are multiple CRE-binding proteins, which vary in size in cell lines derived from different tissues and animal species. To examine the molecular diversity of CREB-327 and related proteins at the nucleic acid level, we used labeled cDNAs from human placenta that encode two different CRE-binding proteins (CREB-327 and CRE-BP1) to probe Northern and Southern blots. Both probes hybridized to multiple fragments on Southern blots of genomic DNA from various species. Alternatively, when a human placental c-jun probe was hybridized to the same blot, a single fragment was detected in most cases, consistent with the intronless nature of the human c-jun gene. The CREB-327 probe hybridized to multiple mRNAs, derived from human placenta, ranging in size from 2-9 kilobases. In contrast, the CRE-BP1 probe identified a single 4-kilobase mRNA. Sequence analyses of several overlapping human genomic cosmid clones containing CREB-327 sequences in conjunction with polymerase chain reaction indicates that the CREB-327/341 cDNAs are composed of at least eight or nine exons, and analyses of human placental cDNAs provide direct evidence for at least one alternatively spliced exon. Analyses of mouse/hamster-human hybridoma DNAs by Southern blotting and polymerase chain reaction localizes the CREB-327/341 gene to human chromosome 2. The results indicate that there is a dichotomy of CREB-like proteins, those that are related by overall structure and DNA-binding specificity as well as those that are related by close similarities of primary sequences.

Plataforma de correo y entorno colaborativo open source

Desplegar una solución fiable, potente y escalable de correo electrónico, en combinación de un entorno colaborativo de aplicaciones, bajo el apadrinamiento de software open source.

Analysis and chromosomal mapping of Leishmania (Leishmania) amazonensis amastigote expressed sequence tags

The characterization of expressed sequence tags (ESTs) generated from a cDNA library of Leishmania (Leishmania) amazonensis amastigotes is described. The sequencing of 93 clones generated new L. (L.) amazonensis ESTs from which 32% are not related to any other sequences in database and 68% presented significant similarities to known genes. The chromosome localization of some L. (L.) amazonensis ESTs was also determined in L. (L.) amazonensis and L. (L.) major. The characterization of these ESTs is suitable for the genome physical mapping, as well as for the identification of genes encoding cysteine proteinases implicated with protective immune responses in leishmaniasis.

Mapping the molecular characteristics of Brazilian human T-cell lymphotropic virus type 1 Env (gp46) and Pol amino acid sequences for vaccine design

This study was carried out to evaluate the molecular pattern of all available Brazilian human T-cell lymphotropic virus type 1 Env (n = 15) and Pol (n = 43) nucleotide sequences via epitope prediction, physico-chemical analysis, and protein potential sites identification, giving support to the Brazilian AIDS vaccine program. In 12 previously described peptides of the Env sequences we found 12 epitopes, while in 4 peptides of the Pol sequences we found 4 epitopes. The total variation on the amino acid composition was 9 and 17% for human leukocyte antigen (HLA) class I and class II Env epitopes, respectively. After analyzing the Pol sequences, results revealed a total amino acid variation of 0.75% for HLA-I and HLA-II epitopes. In 5 of the 12 Env epitopes the physico-chemical analysis demonstrated that the mutations magnified the antigenicity profile. The potential protein domain analysis of Env sequences showed the loss of a CK-2 phosphorylation site caused by D197N mutation in one epitope, and a N-glycosylation site caused by S246Y and V247I mutations in another epitope. Besides, the analysis of selection pressure have found 8 positive selected sites (w = 9.59) using the codon-based substitution models and maximum-likelihood methods. These studies underscore the importance of this Env region for the virus fitness, for the host immune response and, therefore, for the development of vaccine candidates.

Inhibition of mouse mammary tumor virus-induced T cell responses in vivo by antibodies to an open reading frame protein.

Minor lymphocyte stimulating (Mls) antigens specifically stimulate T cell responses that are restricted to particular T cell receptor (TCR) beta chain variable domains. The Mls phenotype is genetically controlled by an open reading frame (orf) located in the 3' long terminal repeat of mouse mammary tumor virus (MMTV); however, the mechanism of action of the orf gene product is unknown. Whereas predicted orf amino acid sequences show strong overall homology, the 20-30 COOH-terminal residues are strikingly polymorphic. This polymorphic region correlates with TCR V beta specificity. We have generated monoclonal antibodies to a synthetic peptide encompassing the 19 COOH-terminal amino acid residues of Mtv-7 orf, which encodes the Mls-1a determinant. We show here that these antibodies block Mls responses in vitro and can interfere specifically with thymic clonal deletion of Mls-1a reactive V beta 6+ T cells in neonatal mice. Furthermore, the antibodies can inhibit V beta 6+ T cell responses in vivo to an infectious MMTV that shares orf sequence homology and TCR specificity with Mtv-7. These results confirm the predicted extracellular localization of the orf COOH terminus and imply that the orf proteins of both endogenous and exogenous MMTV interact directly with TCR V beta.