Pharmacogenetics of anticancer drugs in non-Hodgkin lymphomas

The variability of tumour responses to chemotherapeutic agents is a topic of major interest in current oncology research. Advances in the knowledge of molecular pathology of cancer make available strategies by which tumour cells can be profiled for their genetic background in order to select anticancer agents that might selectively kill cells in a molecular context that matches the mechanism of action of drugs. The next generation of anticancer treatments might thus be tailored on the basis of the numerous molecular alterations identified in tumour cells of a particular patient. However, to exploit these alterations, it is necessary to understand how they influence the cellular pathways that control the sensitivity or, conversely, resistance to chemotherapeutic agents. The aim of this article is to outline major genetic abnormalities in non-Hodgkin lymphomas that can be used to streamline anticancer drug selection and to underscore the major role of pharmacogenetics, which studies the interactions between genetic background and drug activity, to the prediction of likelihood of response and identification of potential new targets for pharmacological intervention. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Seismic Anisotropy beneath Northern Victoria Land from SKS Splitting Analysis

Abstract. Teleseismic data recorded by temporary and permanent stations located in the Northern Victoria Land region are analysed in order to identify the presence and location of seismic anisotropy. We work on data recorded by 24 temporary seismographic stations deployed between 1993 and 2000 in different zones of the Northern Victoria Land, and by the permanent very broad-band stations TNV located near the Italian Base M. Zucchelli. The temporary networks monitored an area extending from Terra Nova Bay towards the South beyond the David Glacier and up to the Indian Ocean northward. To better constrain our study, we also provide an analysis of data recorded by TNV in the same period of time and we take into account also SKS shear wave splitting measurements performed by Barruol and Hoffman (1999) on data recorded by DRV. This study, to be considered as preliminary, reveals the presence of seismic anisotropy below the study region, with a mainly NW-SE fast velocity direction below the Terra Nova Bay area and rather large delay times, that mean a deep rooted anisotropic layer

The institutional choices of politicians : how and why legislators shape Lower Chambers

Cette thèse s’intéresse aux choix institutionnels des législateurs. Elle propose une analyse diachronique et comparative du développement des Chambre Nationale des Députés argentines et chiliennes des années 1940 aux années 2000. Inspiré de la théorie du Cartel (Cox et McCubbins, 1993), ce travail se concentre sur le rôle des partis politiques dans ce développement institutionnel. Il montre qu’en dépit de leurs différences, les partis uniques, coalitions, forces majoritaires ou minoritaires qui ont dirigé ces chambres ont adopté un large éventail de règles et de normes organisationnelles qui les avantagent. Ils se sont, en un mot, comportés comme des coalitions procédurales. L’analyse des modifications des règles de fonctionnement de ces chambres et de leurs systèmes de direction et de commissions montre que les partis et coalitions au pouvoir ont, pendant cette période, renforcé leur pouvoir, contrôlé l’agenda législatif, structuré les systèmes de commission et adopté des règles qui leur ont profité. Les résultats obtenus suggèrent en particulier que les coalitions qui ont dirigé la chambre Chilienne ont installé certains de leurs membres à plusieurs postes comme les présidences d’assemblée et de commissions. Ils montrent l’existence d’un pouvoir de véto sur l’agenda législative plus importante au Chili qu’en Argentine. L’étude du cas argentin montre que les partis au pouvoir ont, en particulier depuis les années 1960, conservé le contrôle de la chambre, non seulement en modifiant les règles et les structures du système de commissions, mais également en créant et distribuant à l’opposition des postes permanents mais sans réel pouvoir. Cette analyse confirme également les résultats obtenus par de récentes études concernant ce champ de recherche, notamment le professionnalisme du système de commission chilien et le caractère amateur des législateurs argentins. A l’inverse, elle met à jour des différences, négligées jusqu’alors, entre l’Argentine et le Chili concernant le contrôle de l’agenda législatif. Cette thèse est divisée en sept chapitres. Le premier introduit le sujet, l’hypothèse générale et les questions posées par la thèse, en expliquant également pourquoi les choix institutionnels des législateurs importent. Le chapitre II présente la théorie et la méthodologie. Il propose une définition du développement institutionnel et explicite les prédictions et critères permettant de tester l’hypothèse générale. Les chapitre III et IV, qui concernent respectivement l’Argentine et le Chili, décrivent le système politique de chaque pays et l’organisation des chambres durant la période étudiée. Les chapitre IV et VI, respectivement pour l’Argentine et le Chili, analysent les réformes des règles régissant les chambres, l’évolution de l’autorité qui les dirige et celle du système de commission. Ces chapitres se concluent par un résumé des différents schémas mis en évidence et une évaluation préliminaire de l’hypothèse générale. En conclusion, le chapitre VII résume les découvertes, donne un verdict global sur la fécondité de la théorie et suggère de nouvelles pistes de recherche.This thesis is about the institutional choices of legislators. It provides a comparative and diachronic analysis of the institutional development of the National Chambers of Deputies of Argentina and Chile from the 1940s to the 2000s. Based on Cartel Theory (Cox and McCubbins 1993), it focuses on the role played by parties in this institutional development. It demonstrates that despite their differences, the various majorities and pluralities, single-parties and coalitions that ruled these Chambers have maintained and adopted a constellation of organizational rules and norms that advantaged their interests. In other words, they have behaved as procedural coalitions. The analysis of the reforms to the rules of these Chambers and of their directing board and committee systems indicates that ruling parties and coalitions have increased their power during the period, controlled the legislative agenda, structured the committee system, and adopted rules that benefit them on the floor. In particular, the results suggest that Chilean ruling coalitions have endowed several offices, such as the Presidency, the Chairs of committees, the committee on Finance (Hacienda) and on Rules, with negative agenda-setting power, and that some of them are more powerful than their Argentine’s counterparts. In the case of the Argentine Chamber, specifically since the 1960s, ruling parties have kept control of the Chamber not only by reforming the rules and structuring the committee system but also creating and distributing powerless but permanent positions to the opposition. The analysis also confirms previous findings made by recent studies in the subfield, specially the professionalism of the Chilean Committee system and the amateur character of Argentine legislators. By contrast, it shows differences in the agenda control between the Argentine and Chilean Chambers that were overlooked. The thesis is divided into seven chapters. Chapter I introduces the general hypothesis, the purposes and main questions of the thesis, and explains why the institutional choices of legislators matter. Chapter II presents the theory and the methodology. It provides the definition of institutional development and the criteria and predictions used to test the general hypothesis. Chapters III (Argentina) and V (Chile) offer an account of each country’s politics and a description of the Chambers’ organization during the period. Chapters IV (Argentina) and VI (Chile) analyze the reforms to the rules of the Chambers, and the evolution of the directing board and committee systems and conclude with a summary of the patterns found and a preliminary assessment of the general hypothesis. Chapter VII concludes. It sums up the findings, provides a final assessment of the theory, and suggests further avenues of research

Joint geophysical observations of ice stream dynamics

Ice streams play a major role in the ice mass balance and in the reckoning of the global sea level; they have therefore been object of wide scientific interest in the last three decades. During the 21st Italian Antarctic Expedition, in the austral summer 2005-06, we deployed a joint seismographic and geodetic network in the area of the David Glacier, Southern Victoria Land. This campaign followed a similar experiment carried out in the same area during the austral summer 2003-04 with the deployment of a seismographic network that recorded significant microseismicity beneath the David Glacier, primarily occurring as a few small clusters. In the latest 2005-06 deployment, 7 seismographic stations and 3 GPS geodetic receivers operated continuously for a period of 3 months (November 2005-early February 2006) in an area of about 100x150 km2 around the David Glacier. We have carried out several analyses using the combined data sets. These included the examination of the temporal evolution in earthquake magnitude and location and also the contemporaneous observation of both seismic activity and surface kinematics of the ice stream to possibly correlate the recorded microseismicity with the movement of the glacier, affected by the Ross Sea tides. Here we present some details of the two temporary networks and preliminary results and implications

Posttransplant lymphoproliferative disorders in neuronal xenotransplanted macaques

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction

(Poly)phenolic content and profile and antioxidant capacity of whole-grain cookies are better estimated by simulated digestion than chemical extraction

It is widely recognized that the biological effects of phytochemicals cannot be attributed to the native compounds present in foods but rather to their metabolites endogenously released after intake. Bioavailability depends on bioaccessibility, which is the amount of the food constituent that is released from the matrix in the gastrointestinal tract. The use of chemical extraction to evaluate the content and profile of phytochemicals does not mirror the physiological situation in vivo, and their bioaccessibility should be considered while assessing their nutritional significance in human health. The current study was designed to compare the (poly)phenolic profile and content and antioxidant capacity of whole-grain (WG) cookies using chemical extraction and a more physiological approach based on simulated digestion. Three types of organic WG cookies (made with durum, Italian khorasan, or KAMUT\uae khorasan wheat) were considered, either fermented by Saccharomyces Cerevisiae or sourdough. Although the flour type and the fermentation process influenced the release of phytochemicals from the cookie matrix, in almost all samples, the simulated digestion appeared the most efficient procedure. Our results indicate that the use of chemical extraction for evaluation of the phytochemicals content and antioxidant capacity of food could lead to underestimation and underline the need for more physiological extraction methods

Micro Finite Element models of the vertebral body: Validation of local displacement predictions

The estimation of local and structural mechanical properties of bones with micro Finite Element (microFE) models based on Micro Computed Tomography images depends on the quality bone geometry is captured, reconstructed and modelled. The aim of this study was to validate microFE models predictions of local displacements for vertebral bodies and to evaluate the effect of the elastic tissue modulus on model’s predictions of axial forces. Four porcine thoracic vertebrae were axially compressed in situ, in a step-wise fashion and scanned at approximately 39μm resolution in preloaded and loaded conditions. A global digital volume correlation (DVC) approach was used to compute the full-field displacements. Homogeneous, isotropic and linear elastic microFE models were generated with boundary conditions assigned from the interpolated displacement field measured from the DVC. Measured and predicted local displacements were compared for the cortical and trabecular compartments in the middle of the specimens. Models were run with two different tissue moduli defined from microindentation data (12.0GPa) and a back-calculation procedure (4.6GPa). The predicted sum of axial reaction forces was compared to the experimental values for each specimen. MicroFE models predicted more than 87% of the variation in the displacement measurements (R2 = 0.87–0.99). However, model predictions of axial forces were largely overestimated (80–369%) for a tissue modulus of 12.0GPa, whereas differences in the range 10–80% were found for a back-calculated tissue modulus. The specimen with the lowest density showed a large number of elements strained beyond yield and the highest predictive errors. This study shows that the simplest microFE models can accurately predict quantitatively the local displacements and qualitatively the strain distribution within the vertebral body, independently from the considered bone types

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

Objective: Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens

Joint Geophysical Observations of Ice Stream Dynamics

Ice streams play a major role in the ice mass balance and in the reckoning of the global sea level; they have therefore been object of wide scientific interest in the last three decades. During the 21st Italian Antarctic Expedition, in the austral summer 2005–06, we deployed a joint seismographic and geodetic network in the area of the David Glacier, Southern Victoria Land. This campaign followed a similar experiment carried out in the same area during the austral summer 2003–04 with the deployment of a seismographic network that recorded significant microseismicity beneath the David Glacier, primarily occurring as a few small clusters. In the latest 2005–06 deployment, 7 seismographic stations and 3 GPS geodetic receivers operated continuously for a period of 3 months (November 2005–early February 2006) in an area of about 100×150 km2 around the David Glacier. We have carried out several analyses using the combined data sets. These included the examination of the temporal evolution in earthquake magnitude and location and also the contemporaneous observation of both seismic activity and surface kinematics of the ice stream to possibly correlate the recorded microseismicity with the movement of the glacier, affected by the Ross Sea tides. Unfortunately, a clear correlation between the occurrence of seismic events and the movement of the glacier is not evident. Here we present some details of the two temporary networks and preliminary results and implications