Existing treatments for mantle cell lymphoma (MCL) are non-curative, demonstrating a need for a refined treatment approach. Recent clinical trials have shown promising results with the use of mammalian target of rapamycin inhibitors. I hypothesize that the anti-tumor effect of mTOR inhibitors in mantle cell lymphoma is mediated by an increase in manganese superoxide dismutase (MnSOD) protein expression and accumulation of hydrogen peroxide (H₂O₂). Findings indicate that the rapamycin-induced cytostatic effect is characterized by increased levels of MnSOD and H₂O₂, and is necessary for the full growth inhibitory effect of rapamycin. Furthermore, over-expression of MnSOD elevated the level of H₂O₂ and increased sensitivity to MnSOD. Treatment with rapamycin resulted in a loss of serine 473 phosphorylation of AKT and increased levels of MnSOD were found to be due to inhibition of the mTORC2 complex. These results are the first to suggest that long term treatment of MCL cells with rapamycin inhibits the mTORC2 complex. By understanding the key signaling molecules and affected pathways in the anti-tumor effects of mTOR inhibitors, we may be able to identify additional predictive markers to improve the therapeutic value, or study drug combinations that will enhance the effect of ROSinduced cytotoxicity. A retrospective study utilizing samples from lymphoma patients receiving standard anthracycline-based therapies, identified single nucleotide polymorphisms in oxidative stressrelated genes associated with survival. Individuals carrying minor allele SNPs in myeloperoxidase (MPO) and an aldo-keto reductase (AKR1C3) were found to be associated with shorter time to disease progression and death. This data suggest that some patients may benefit from a different therapy than the current standard of care and that regulation of the redox environment plays a role in aggressive lymphoma treatment response.

The 62 million year old lava flows of Baffin Island and West Greenland represent the earliest phase of magmatism in the North Atlantic Igneous Province (NAIP). These picritic lavas are characterised by high magnesium contents owing to their high proportion of olivine crystals. The parental magmas for the picrites are likely to have accumulated olivine crystals on their transit through the lithosphere and crust. Debate over the origin of accumulated crystals in the lavas results in uncertainty in the temperature and composition of the parental magmas for the early NAIP. The magnesium-rich olivine crystals (up to Fo93) in the picrites of this study are shown not to have a xenocrystic origin. The samples, therefore, support the inference of high potential temperatures for the Baffin Island-West Greenland magmas, ~200oC above ambient mantle. The picrites of Baffin Island and West Greenland display the highest terrestrial magmatic 3He/4He (up to 50 Ra, where Ra is the atmospheric value 1.39 x 10-6), values that are considerably higher than the highest 3He/4He in contemporary ocean island basalts, which reach a maximum of ~30 Ra. High 3He/4He in Baffin Island and West Greenland are associated with a wide range of incompatible trace element and lithophile radiogenic isotopic compositions, not dissimilar to the range of compositions displayed by lavas at mid-ocean ridges, and overlapping the range displayed by most northern hemisphere ocean island basalts. Crustal contamination modelling in which high-grade Proterozoic crustal basement rocks are mixed with depleted parents cannot account for the compositional trends displayed by the picrites. Major and trace element compositions were determined on melt inclusions in high- 3He/4He picrites that span a wide range of whole-rock incompatible trace element and radiogenic isotopic compositions. The melt inclusions support the findings from the whole-rock study since melt inclusion compositions reflect the composition of their associated whole-rock, with no anomalous compositions present. In addition, there is no evidence for a contribution of a proportion of depleted melts to the source of the relatively enriched whole-rock samples. Therefore, since all melt inclusions were contained within high-3He/4He samples, it is shown that high 3He/4He is a feature of both depleted and relatively enriched melt compositions. The wide range in whole-rock compositions of the Baffin Island and West Greenland picrites represents that of the sub-lithospheric mantle source region and is inconsistent with derivation of the picrites from residues of ancient mantle depletion. The apparent decoupling of helium from trace elements and radiogenic isotopes is hard to reconcile with simple mixing of a high-helium concentration, high-3He/4He reservoir with various depleted and enriched helium-poor mantle reservoirs. It is possible that primordial helium has diffused into a reservoir with a composition similar to that of the convecting upper mantle. However, this must have occurred after the development of existing mantle heterogeneity. The high-3He/4He picrites require the existence of a deep, primordial helium-rich reservoir. Whether this reservoir is present in the upper or deep mantle, or even the core, remains uncertain.

Mantle pyroxenites are important components of mantle rocks, because they provide important insights into bulk composition and heterogeneity of the Earth's upper mantle and therefore, direct evidence of mantle evolution throughout the Earth history. Studied pyroxenites from localities Bečváry (the Kutná Hora Complex), Níhov, Nové Dvory, Mohelno, Horní Kounice, Karlstteten and Meidling (the Gföhl Unit of the Moldanubian Zone) occur as dykes and/or layers within spinel and garnet peridotites from the Bohemian massif. Whole-rock concentrations of rare earth (REE) and other trace elements in studied pyroxenites yield extreme variability, which most likely reflect: 1) variable garnet/clinopyroxene ratios in bulk rocks, 2) different degree of fractionation of parental melts and 3) different concentrations trace elements in the source host material. Pyroxenites from locality Mohelno (LREE-depleted) may be derived from depleted or only slightly enriched suboceanic mantle. In contrast, pyroxenites from Karlstetten, Meidling, Horní Kounice and Nové Dvory (LREE-enriched) crystallized from the melts derived from enriched mantle source with possibly significant contribution of recycled crust. Studied pyroxenites are characterized by extremely variable 187 Os/188 Os ratios. While the pyroxenites from Mohelno and...

The general aim of this thesis is to investigate heterogeneity in the structure of the crust and uppermost mantle of Archaean and Proterozoic terrains in southern Africa and to use the findings to advance our understanding of Precambrian crustal genesis. Teleseismic, regional and local seismic recordings by the broadband stations of the Southern African Seismic Experiment (SASE), Kimberley array, South African National Seismograph Network (SANSN) and the Global Seismic Network (GSN) are used in the inversion procedures to address the aim of this thesis. In the first part of the thesis, the nature of the lower crust across the southern African shield is investigated by jointly inverting receiver functions and Rayleigh wave group velocities. The resultant Vs models show that much of southern Africa has a lower crust that is mafic in composition, whereas the western parts of the Kaapvaal and Zimbabwe Cratons have a lower crust that is intermediate-to-felsic in composition probably due to rifting. The second part of the thesis evaluates the “dipping-sheet” and “continuous-sheet” models of the Bushveld Complex using better-resolved seismic models derived in a two-step approach, employing high-frequency Rayleigh wave group velocity tomography and the joint inversion of high-frequency receiver functions and 2–60 sec Rayleigh wave group velocities. The resultant seismic models favor a “continuous-sheet” model of the Bushveld Complex, although detailed modelling near the centre of the Complex shows that the subsurface mafic layering could be disrupted. The third part of the thesis, is focused on jointly inverting high-frequency teleseismic receiver functions and 10–60 sec Rayleigh wave group velocities to place shear wave velocity constraints on the source of the Beattie Magnetic Anomaly (BMA) at depth and to evaluate existing geophysical models of the BMA source. The resultant Vs models across the BMA suggest the BMA source to be at upper to middle crustal depths (5–20 km) with high velocity layers (≥ 3.5 km/s). Further to this, is a lower crust that is highly mafic (Vs ≥ 4.0 km/s) and a crust beneath the BMA that is on average thicker than 40 km. Plausible models of the BMA source are massive sulphide ore bodies and/or mineralized granulite-facies mid-crustal rocks and/or mineralized Proterozoic anorthosites. v Overall, the findings in this research project are consistent with the broad features of a previous model of Precambrian lithospheric evolution but allows for refinements of that model.

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy. October 2017. / Since the arc assembly and continental collision of the East African Orogen some 640 million years ago, Madagascar has gone through several geodynamic and tectonic episodes that have formed and subsequently modified its lithosphere. This thesis aims to investigate the structure of the crust, the uppermost mantle, and the mantle transition zone beneath Madagascar to gain insights into the relationship between present-day lithosphere structure and tectonic evolution, and to evaluate candidate models for the origin of the Cenozoic intraplate volcanism. To address these issues, local, regional, and teleseismic events recorded by several temporary seismic networks; the MAdagascar-COmoros-MOzambique (MACOMO), the SEismological signatures in the Lithosphere/Asthenosphere system of SOuthern MAdagascar (SELASOMA), and the Réunion Hotspot and Upper Mantle – Réunions Unterer Mantel (RHUM-RUM) were used to complement the seismic events recorded by the permanent seismic stations in Madagascar. The different methods used and the primary results of this study are explained in each section of this thesis. In the first part of this thesis, crustal and uppermost mantle structure beneath Madagascar was studied by analyzing receiver functions using an H-κ stacking technique and a joint inversion with Rayleigh-wave phase-velocity measurements. Results reflect the eastward and northward progressive development of the western sedimentary basins of Madagascar. The thickness of the Malagasy crust ranges between 18 km and 46 km. The thinnest crust (18-36 km thick) is located beneath the western basins and it is due to the Mesozoic rifting of Madagascar from eastern Africa. The slight thinning of the crust (31-36 km thick) along the east coast may have been caused by crustal uplift and erosion when Madagascar moved over the Marion hotspot and India broke away from it. The parameters describing the crustal structure of Archean and Proterozoic terranes, including thickness, Poisson’s ratio, average shear-wave velocity, thickness of mafic lower crust, show little evidence of secular variation. Slow shear-wave velocity of the uppermost mantle (4.2-4.3 km/s) are observed beneath the northern tip, central part and southwestern region of the island, which encompass major Cenozoic volcanic provinces in Madagascar. The second part of the thesis describes a seismic tomography study that determines the lateral variation of Pn-wave velocity and anisotropy within the uppermost mantle beneath Madagascar. Results show an average uppermost mantle Pn-velocity of 8.1 km/s. However, zones of relatively low-Pn-velocity (~7.9 km/s) are found beneath the Cenozoic volcanic provinces in the northern, central, and southwestern region of the island. These low-Pn-velocity zones are attributed to thermal anomalies that are associated with upwelling of hot mantle materials that gave rise to the Cenozoic volcanism. The direction of Pn anisotropy shows a dominant NW-SE direction of fast-polarization in the northern region and around the Ranostara shear zone, in the south-central Madagascar. The anisotropy in the uppermost mantle beneath these regions aligns with the existing geological framework, e.g. volcanic complex and shear zones, and can be attributed to a fossil anisotropy. The Pn anisotropy in the southwestern region, around the Morondava basin, is E-W to NE-SW-oriented. It can be attributed either to the mantle flow from plate motion, the African superplume, or the Mesozoic rifting from Africa. Results from this study do not show any substantial evidence of the formation of a diffuse boundary of the Lwandle plate, cutting through the central region of Madagascar. Station static delays reflect the significant variation in the Moho depth beneath the island. In the third part of the thesis, the thickness of the mantle transition zone beneath Madagascar, which is sensitive to the surrounding temperature variation, has been estimated by stacking receiver functions. Single-station and common-conversionpoint stacking procedures show no detectable thinning of the mantle transition zone and thus no evidence for a thermal anomaly in the mantle under Madagascar that extends as deep as the mantle transition zone. Therefore, this study supports an upper mantle origin for the Cenozoic volcanism. However, the resolution of the study is not sufficient to rule out the presence of a narrow thermal anomaly as might arise from a plume tail. Overall, the findings in this research are broadly consistent with the crustal and upper mantle structure of Madagascar determined by previous studies, but provides significantly greater detail with regard to the crustal and uppermost mantle structure as more seismic stations were used. / LG2018

Thesis advisor: John E. Ebel / Thesis advisor: John C. Hepburn / Using the seismic refraction technique with a least squares inversion methodology, arrival time data from 1985 to the present are analyzed to delineate, with improved spatial resolution, the upper mantle P-velocity structure throughout northeastern North America (NENA). A total of one hundred and sixty-eight earthquakes are analyzed utilizing over one hundred seismic stations throughout NENA. Seismic data analyzed between 200 - 400 km, 400 - 600 km, and 600+ km throughout NENA are used to study the increase in velocity with depth in the upper mantle. A jackknife analysis was carried out to put constraints on the uncertainties of the velocity measurements. The P-wave velocity of the upper mantle through the New England Appalachians is found to be uniformly 7.94 - 8.07 km/s at depths down to 75 km. Upper mantle Pn velocities throughout the southeastern Grenville Province show velocities ranging from 8.15 km/s to 8.54 km/s as epicentral distances increase. Uncertainties of P velocities range from 0.01- 0.12 km/s. Based on laboratory measurements of simulated upper mantle conditions and the orogenic history of the Grenville Province and northern Appalachians, upper mantle mineral compositions of eclogite (Grenville Province) and pyroxenite (northern Appalachians) are proposed to be the factor controlling seismic velocity variation in the upper mantle. Variations in upper mantle temperatures between the Grenville Province and northern Appalachians are ruled out as affecting the difference in upper mantle velocities between southeastern Canada and New England. / Thesis (MS) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Geology and Geophysics.

In this dissertation, I use seismic imaging methods to constrain the evolution of the oceanic upper mantle across the Juan de Fuca (JdF) and Gorda plates. This work begins by studying the geometry of the mantle magmatic system and patterns of mantle flow beneath the northern JdF ridge in relation to ridge-parallel changes in accretionary processes. I find that the dynamics of lithospheric rifting exert the primary control on the distribution of shallow mantle melts and variations in crustal thickness and composition. The orientation of mantle divergence beneath the JdF ridge, as inferred from seismic anisotropy, is oblique to the overlying plate divergence direction. Similar observations made at the East Pacific Rise and Mid-Atlantic ridge suggest plate motions alone do not control mantle flow patterns. On the contrary, stresses exerted at the base of the plate by the asthenospheric flow field may contribute to changes in plate motion prompting a reorientation of oceanic spreading segments. The mantle anisotropic fabric of the JdF plate interior is then investigated to identify whether the rotated mantle flow field observed beneath the JdF ridge persisted throughout the recent geologic past. However, observations suggest that the anisotropic structure created at the ridge partially reorganizes off-axis obscuring the paleo-flow geometry. Next, I focus on how the physical state of the oceanic lithosphere evolves with time. Using local earthquake arrival times I test whether the seismic velocity structure of the upper mantle lithosphere is thermally controlled or dominated by heterogeneities introduced upon accretion at the ridge or by subsequent deformation off axis. Despite extensive surficial evidence of faulting across the Gorda plate, deformation appears to be restricted to crustal depths and mantle velocities are explained by conductive cooling. In contrast, the velocity structure of the JdF plate is inconsistent with conductively-cooled mantle. Hydration of the mantle lithosphere associated with tectonic discontinuities is invoked to explain anomalously slow P-wave speeds. Lastly, a joint inversion of teleseismic body and surface wave data is proposed to image the geometry of mantle upwelling and melt production beneath the JdF and Gorda Ridges. This dissertation includes previously published and unpublished coauthored material.

Mantle Cell Lymphoma (MCL) is a rare but aggressive Non-Hodgkin Lymphoma (NHL). Although t(11;14) is a hallmark of MCL, it is insufficient for lymphomagenesis. The phosphoinositide-3 kinase (PI3K) pathway is thought to play an important role in MCL pathogenesis and the PI3K p110δ isoform is enriched in leucocytes making it an attractive target. Early phase trials evaluating the p110δ selective inhibitor GS-1101 however demonstrate inferior responses in MCL compared to chronic lymphocytic leukaemia and indolent NHL. The relative contribution of the class Ia PI3K isoforms p110α (PIK3CA), p110β (PIK3CB) and p110δ (PIK3CD) was therefore evaluated in MCL. Immunohistochemistry on MCL tissue microarrays revealed that while p110δ was highly expressed, p110α showed wide variation and p110β expression was the weakest. A significant increase in p110α expression was found with disease progression. Although GS-1101 was sufficient to abolish B-cell receptor mediated PI3K activation, additional p110α inhibition was necessary to abolish constitutive PI3K activation in MCL exhibiting high p110α expression. Compared to GS-1101, GDC-0941 (p110α and p110δ inhibitor) had greater in vitro toxicity and a high PIK3CA/PIK3CD mRNA ratio (> twice ratio in healthy B-cells) was able to identify primary MCL samples that were resistant to GS-1101 but significantly more sensitive to GDC—0941. This ratio also increased with disease progression. No PIK3CA or PIK3R1 activating mutations were found. In summary, blockade of both p110α and p110δ appears to be necessary for effective PI3K inhibition in MCL, particularly with relapse. The PIK3CA/PIK3CD mRNA ratio may help identify those patients that are most likely to respond. Finally, a disseminated xenograft model of human primary MCL was established in NSG mice. Engraftment of primary MCL was demonstrated by peripheral blood flow cytometry, tissue immunohistochemistry and FISH for t(11;14). This model is potentially valuable for pre-clinical in vivo testing of novel drugs for this incurable disease.

Constituant la couche limite supérieure de la convection mantellique, la lithosphère terrestre est à l'interface entre les enveloppes externes et internes de notre Planète. Les interactions multiples entre celle-ci et le manteau sont à l'origine de déformations latérales (tectonique des plaques) et verticales (topographie dynamique) de la surface terrestre. Comprendre comment la formation et l'évolution d'instabilités convectives mantelliques renouvellent sans-cesse la surface est donc primordial pour améliorer nos interprétations d'un grand nombre d'observations de surface, telles que la formation de bassins sédimentaires, le mouvement des continents, la localisation des points chauds, la formation d'anomalies gravimétriques ou encore les variations du niveau marin.Cette thèse propose de développer des modèles numériques de convection mantellique générant defaçon auto-organisée de la tectonique des plaques en surface an d'étudier la façon dont le développement et la dynamique d'instabilités convectives telles que les panneaux de subduction ou les panaches mantelliques modifient la surface, dans un contexte de tectonique de surface approchant le régime terrestre.Dans une première partie, je m'intéresse à l'influence du couplage des mouvements de convection mantellique et de tectonique des plaques sur le développement de topographie dynamique (i.e. les mouvements verticaux de la lithosphère induits par la convection mantellique) à différentes échelles spatio-temporelles. Mes résultats suggèrent que la surface terrestre peut se déformer à toutes les échelles spatiales, du fait de mouvements convectifs de grande ampleur faisant intervenir le manteau entier (> 104 km) ou encore de convection à petite échelle sub-lithosphérique (< 500 km). Les variations temporelles de topographie dynamique s‘étendent de cinq à plusieurs centaines de millions d'années selon la nature des processus convectifs dont elles dérivent. En particulier, la dynamique d'initiation ou d'arrêt des zones de subduction contrôle l'existence d'échelles intermédiaires de topographie dynamique (longueurs d'onde variant entre 500 et 104 km). Ces résultats montrent donc que les interactions entre la dynamique de la lithosphère et la convection mantellique génèrent des motifs spatio-temporels de topographie dynamique complexes et cohérents par rapport aux observations terrestres.Dans un deuxième temps, cette thèse se focalise sur la dynamique des panaches mantelliques, et leurs interactions avec la surface. Je caractérise d'abord précisement le comportement des panaches générés dans nos modèles de convection à la lumière d'observations de surface. Puis, j'étudie la façon dont leurs interactions avec la tectonique de surface et les différentes échelles convectives modifient leurs mouvements latéraux. Enfin, la compréhension de la signature thermique des interactions entre panaches et rides océaniques me permet de proposer une reconstitution des mouvements relatifs entre le panache des Açores et la ride médio-Atlantique. / Earth's lithosphere, which is the upper boundary layer of mantle convection, represents the interface between the external and internal envelopes of our Planet. The multiple interactions between the mantle and lithosphere generate lateral (plate tectonics) and vertical (dynamic topography) deformations of Earth's surface. Understanding the influence of the dynamics of mantle convective instabilities on the surface is fundamental to improve our interpretations of a large range of surface observations, such as the formation of sedimentary basins, continental motions, the location of hotspots, the presence of gravity anomalies or sea-level variations.This thesis aims at developing numerical models of whole-mantle convection self-generating plate-like tectonics in order to study the impacts of the development and the dynamics of mantle convective instabilities (such as slabs or mantle plumes) on the continuous reshaping of the surface.First, I focus on the influence of the coupling between mantle convective motions and plate tectonics on the development of dynamic topography (i.e. surface vertical deformations induced by mantle convection) at different spatial and temporal scales. The results suggest that Earth's surface can deform over large spatial scales (> 104 km) induced by whole-mantle convection to small-scales (< 500 km) arising from small-scale sub-lithospheric convection. The temporal variations of dynamic topography range between five and several hundreds of millions of years depending on the convective instabilities from which they originate. In particular, subduction initiation and slab break-off events control the existence of intermediate scales of dynamic topography (between 500 and 104 km). This reflects that the interplay between mantle convection and lithosphere dynamics generates complex spatial and temporal patterns of dynamic topography consistent with constraints for Earth.A second aim of this thesis is to understand the dynamics of mantle plumes and their interactionswith surface. I first characterize in detail the behaviour of mantle plumes arising in models ofwhole-mantle convection self-generating plate-like tectonics, in light of surface observations. Then, I study how the interactions between surface plate tectonics and mantle convection affect plume motions. Finally, I use observations of the thermal signature of plume/ridge interactions to propose a reconstruction of the relative motions between the Azores mantle plume and the Mid-Atlantic Ridge.

The České středohoří Mts. forming the most important and active part of Ohře/Eger rift are formed by volcanic rocks of Tertiary age containing upper mantle xenoliths which can provide us information about internal structure of upper mantle. This diploma thesis is focused on the study of mantle xenoliths from this part of Bohemian massif close to the city Litoměřice (4 locations: Dobkovičky, Prackovice, Kuzov, Medvědí hill) and for comparison another 4 locations of mantle xenoliths from the northern Bohemia locaties Brtníky in Šluknovský ledge, Kraslice and Zámeček at Fláje in Krušné Mts. and Venuše volcano in Nízký Jeseník at Bruntálská Highlands. Almost all studied xenoliths are spinel harzburgites or lherzolites with mineral association olivine + orthopyroxene + clinopyroxene + spinel (the most often Cr-spinel). They have usually protogranular texture followed by porfyroclastic texture (porfyroclasts are represented by olivine, orthopyroxene and in some cases also by clinopyroxene, and fine-grained matrix of all these minerals with olivine showing undulose extinguishes). An equigranular texture is the least common. Host rock of the xenoliths is always basanite. The most abundant mineral in peridotite xenoliths is olivine with #Mg value 89,4-91,5; followed by orthopyroxene with #Mg value 90,8-92,1...