Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06).

BACKGROUND: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease, and Child-Pugh class A or mild Child-Pugh class B liver dysfunction. Patients received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). RESULTS: Forty-five patients were enrolled. The median age was 63 years; 89% had Child-Pugh class A disease and 47% had distant metastases. PFS12 was rated successful in 15 patients (33%; 95% confidence interval, 20%-47%). Over the whole trial period, one complete response and a 40% rate of stable disease as the best response were achieved. The median PFS duration, disease stabilization duration, time to progression, and overall survival time were 1.5, 2.9, 1.5, and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent. None of the 33 deaths were considered drug related. CONCLUSION: Continuous SU treatment with 37.5 mg daily is feasible and has moderate activity in patients with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design (>13 PFS12 successes), the therapy is considered promising. This is the first trial describing the clinical effects of continuous dosing of SU in HCC patients on a schedule that is used in an ongoing, randomized, phase III trial in comparison with the current treatment standard, sorafenib (ClinicalTrials.gov identifier, NCT00699374).

Antibody-conjugated MHC class I tetramers can target tumor cells for specific lysis by T lymphocytes.

To demonstrate that antibody-guided targeting of antigenic MHC class I-peptide tetramer on tumor cells can render them susceptible to lysis by relevant cytotoxic T lymphocytes (CTL), biotinylated HLA-A*0201/Flu matrix peptide complexes were tetramerized on streptavidin molecules previously coupled to Fab' fragments from monoclonal antibodies (mAb) specific for cell surface markers such as carcinoembryonic antigen (CEA), ErbB-2 or CD20. Flow cytometry analysis showed that coating of the HLA-A2-peptide complexes on the four HLA-A2-negative human cancer lines tested (including a CEA-positive colon carcinoma, an ErbB-2(+) breast carcinoma and two CD20(+) B lymphomas) was entirely dependent upon the specificity of the conjugated antibody fragments. More importantly, HLA-A2-restricted Flu matrix peptide-specific CTL were then found to lyse specifically and efficiently the MHC-coated target cells. These results open the way to the development of new immunotherapy strategies based on antibody targeting of MHC class I-peptide complexes.

Marginal adaptation in vitro and clinical outcome of Class V restorations

OBJECTIVES: We examined the correlation between the quantitative margin analysis of two laboratory test methods (Berlin, Zurich) and the clinical outcome in Class V restorations. METHODS: Prospective clinical studies with an observation period of at least 18 months were searched in the literature, for which laboratory data were also available. The clinical outcome variables were retention loss, marginal discoloration, detectable margins and secondary caries. Forty-four clinical studies matched the inclusion criteria, including 34 adhesive systems for which laboratory data were also present. For both laboratory test methods and the clinical studies, an index was formulated to better compare the in vitro and in vivo results. Linear mixed models which included a random study effect were calculated. As most clinical data were available for 12 and 24 months, the main analysis was restricted to these recall intervals. RESULTS: The comparative analysis revealed a weak correlation between the clinical index and both in vitro indices. The correlation was statistically significant for the Berlin method but not for the Zurich method and only present if studies were compared which used the same composite in the in vitro and in vivo study. When defining specific cut-off values, the prognosis for the good clinical performance of an adhesive system based on in vitro results was 78% (Berlin) or 100% (Zurich). For poor performance it was 67% and 60%, respectively. No correlation was found between both in vitro methods. SIGNIFICANCE: The surrogate parameter "marginal adaptation" of restorations placed in extracted teeth has a mediocre value to predict the clinical performance of an adhesive system in cervical cavities. The composite is an important factor for a successful prediction. The comparison between in vitro/in vivo is sometimes hampered by the great variability of clinical results on the same adhesive system.

Widespread occurrence of non-canonical transcription termination by human RNA polymerase III.

Human RNA polymerase (Pol) III-transcribed genes are thought to share a simple termination signal constituted by four or more consecutive thymidine residues in the coding DNA strand, just downstream of the RNA 3'-end sequence. We found that a large set of human tRNA genes (tDNAs) do not display any T(≥4) stretch within 50 bp of 3'-flanking region. In vitro analysis of tDNAs with a distanced T(≥4) revealed the existence of non-canonical terminators resembling degenerate T(≥5) elements, which ensure significant termination but at the same time allow for the production of Pol III read-through pre-tRNAs with unusually long 3' trailers. A panel of such non-canonical signals was found to direct transcription termination of unusual Pol III-synthesized viral pre-miRNA transcripts in gammaherpesvirus 68-infected cells. Genome-wide location analysis revealed that human Pol III tends to trespass into the 3'-flanking regions of tDNAs, as expected from extensive terminator read-through. The widespread occurrence of partial termination suggests that the Pol III primary transcriptome in mammals is unexpectedly enriched in 3'-trailer sequences with the potential to contribute novel functional ncRNAs.

Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-gamma-induced MHCII expression on a wide variety of non-bone marrow-derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4(+) T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-gamma-activated cells of the macrophage lineage. pIV(-/-) mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

The immunopathology of human schistosomiasis-III: immunoglobulin isotype profiles and response to praziquantel

Immunoglobulin (Ig) isotype (IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgD and IgE) levels were investigated, both pre- and post-treatment with praziquantel (PZQ), in 43 adults and children chronically infected with Schistosoma mansoni , by means of a two-site, isotype-specific immunoenzymometric assay. The patients were classified as responders (R) or non-responders (NR) on the basis of their circumoval precipitin test (COPT) results 12 months after treatment. In comparison with controls, pre-treatment R children showed significantly higher levels of IgG, IgG1, IgG4 (p<0.001) and IgE (p<0.01), and diminished IgG2 (p<0.05), while NR children showed significantly elevated levels only of IgE (p<0.05). Twelve months after therapy, R children maintained significantly lower levels of IgG2, but showed significantly decreased levels of IgG, IgG1, IgG4, and IgE, while the Ig isotype profile of NR children was unaltered. Adult R and NR showed similar isotype profiles before chemotherapy, with the exception of significantly elevated IgM levels in R. Twelve months after therapy, R adults showed significantly decreased levels of IgG, IgG1, and IgG4, while NR adults showed only diminshed IgG4 levels. These results reveal different Ig isotype profiles in untreated adults and children chronically infected with S. mansoni. The results further show that the pre-treatment Ig isotype profile may be significantly modified after an effective R to chemotherapy, accounted for by down regulation of the IgG1 isotype in association with negative seroconversion of the COPT in R patients. The COPT reaction has been associated with the highly specific egg glycoprotein antigen w1, which shows a significant reduction in reactivity six months after treatment. IgG1 may thus play a main role in the response against the w1 antigen.

Aplicacions de reconeixement de la parla: sistemes de respeaking III

En aquest projecte es fa una introducció als reconeixedors de la parla, el seu funcionament i la seva base matemàtica. Un cop tots els conceptes han quedat clars, es mostra el mètode de creació que hem seguit per obtenir el nostre propi reconeixedor de la parla, utilitzant les eines HTK, en català. S’avaluen les seves virtuts i els seus defectes a través de diferents proves realitzades als seus components. A més a més, el projecte arrodoneix la feina implementant un sistema de dictat automàtic que explota el reconeixedor de la parla utilitzant Julius.

La réhabilitation psychosociale a l'aube du XXIème siècle: III: Méthode d'évaluation interdisciplinaire et bilan biopsycho-social

During the past 20 years, therapeutic and rehabilitative modalities in the field of psychosocial rehabilitation have been diversified in becoming more specific. We have the possibility to offer individualized rehabilitation programs as well as in the general field of socio-professional goals as in the clinical field according to the patients' needs and personal assets. The content of these programs associates various forms of specialized medical and paramedical services. The indications are established trough a careful assessment. The rehabilitation unit of the University Department of Psychiatry in Lausanne has developed a multidisciplinary assessment method based on the bio-psychosocial integrative model and the vulnerability-stress model in integrating the level of experience of Wood for the analysis of the psychosocial functioning. This results in a structured assessment program, which leads to a multidisciplinary comprehensive assessment (difficulties versus adaptative resources)

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality.

PURPOSE: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS: Patients (median age 54years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Incoordination, Paralysis and Recovery after Pyrethroid Treatment on Nymphs III of Triatoma infestans (Hemiptera: Reduviidae)

Symptoms of poisoning for deltamethrin and cis-permethrin on nymphs III of Triatoma infestans were described. The time required for incoordination and paralysis were determined. Deltamethrin was equal or more rapid in the onset of the first effect (accordingly to dose), and cis-permethrin in the onset of the second one. There were no significant differences between incoordination doses 50% (IncD50s) at different times for the two pyrethroids. They showed equivalent incoordination power, but the nymphs treated with deltamethrin recovered slightly more rapid and in greater amount than the nymphs treated with cis-permethrin. The recovery was inhibited by the simultaneus application of piperonyl butoxide. This result suggests that biotransformation by mixed-function microsomal oxidases are involved in the process of recovery

Structural prediction of peptides bound to MHC class I.

An ab initio structure prediction approach adapted to the peptide-major histocompatibility complex (MHC) class I system is presented. Based on structure comparisons of a large set of peptide-MHC class I complexes, a molecular dynamics protocol is proposed using simulated annealing (SA) cycles to sample the conformational space of the peptide in its fixed MHC environment. A set of 14 peptide-human leukocyte antigen (HLA) A0201 and 27 peptide-non-HLA A0201 complexes for which X-ray structures are available is used to test the accuracy of the prediction method. For each complex, 1000 peptide conformers are obtained from the SA sampling. A graph theory clustering algorithm based on heavy atom root-mean-square deviation (RMSD) values is applied to the sampled conformers. The clusters are ranked using cluster size, mean effective or conformational free energies, with solvation free energies computed using Generalized Born MV 2 (GB-MV2) and Poisson-Boltzmann (PB) continuum models. The final conformation is chosen as the center of the best-ranked cluster. With conformational free energies, the overall prediction success is 83% using a 1.00 Angstroms crystal RMSD criterion for main-chain atoms, and 76% using a 1.50 Angstroms RMSD criterion for heavy atoms. The prediction success is even higher for the set of 14 peptide-HLA A0201 complexes: 100% of the peptides have main-chain RMSD values &lt; or =1.00 Angstroms and 93% of the peptides have heavy atom RMSD values &lt; or =1.50 Angstroms. This structure prediction method can be applied to complexes of natural or modified antigenic peptides in their MHC environment with the aim to perform rational structure-based optimizations of tumor vaccines.

Synthesis and characterization of a new class of anti-angiogenic agents based on ruthenium clusters.

New triruthenium-carbonyl clusters derivatized with glucose-modified bicyclophosphite ligands have been synthesized. These compounds were found to have cytostatic and cytotoxic activity and depending on the number of bicyclophosphite ligands, and could be tuned for either anti-cancer or specific anti-angiogenic activity. While some compounds had a broad cellular toxicity profile in several cell types others showed endothelial cell specific dose-dependent anti-proliferative and anti-migratory efficacy. A profound inhibition of angiogenesis was also observed in the in vivo chicken chorioallantoic membrane (CAM) model, and consequently, these new compounds have considerable potential in drug design, e.g. for the treatment of cancer.

Paleopatología dental de una muestra esquelética del área funeraria del suburbio oriental de Tarraco (siglo I-III d. C.)

Los dientes son una importante fuente de información en el estudio de poblaciones del pasado. El estudio de las enfermedades dentales en restos esqueléticos antiguos busca reconstruir la forma de vida de las poblaciones antiguas relacionadas con su estado de salud y enfermedad.