Le lymphome de Hodgkin est caractérisé, d’un point de vue histologique, par la présence de rares cellules tumorales nommées cellules de Reed et Sternberg, au sein d’un infiltrat cellulaire polymorphe, inflammatoire et réactionnel. Cette dernière résulte de la transformation tumorale de cellules lymphocytaires B qui acquièrent des propriétés d’échappement au système immun, de prolifération, de résistance à l’apoptose et une instabilité chromosomique. Néanmoins, la rareté des cellules tumorales, impliquant des problèmes techniques mais aussi de caractérisation des évènements primaires dans l’initiation de cette instabilité chromosomique, a été bien débattue dans la littérature. Mais les mécanismes impliqués dans l’instabilité chromosomique dans le lymphome de Hodgkin demeurent obscurs.La première partie de cette thèse a été consacrée à l’étude des mécanismes impliqués dans l’instabilité génomique du lymphome de Hodgkin via l’instabilité des microsatellites et l’instabilité chromosomique en utilisant 7 lignées de lymphome de Hodgkin. Nous avons montré pour la première fois l’implication des microsatellites dans l’instabilité génomique des lymphomes de Hodgkin (MSI-H (microsatellite instability-high) dans 3/7 lignées). De plus, nous avons montré que deux mécanismes favorisent l’émergence d’une instabilité chromosomique : le premier implique une instabilité télomérique qui est présente essentiellement dans les petites cellules tumorales induisant la formation des chromosomes dicentriques, des amplifications des gènes (Jak2 comme exemple) et des arrangements chromosomiques complexes. Le deuxième mécanisme est lié essentiellement à un défaut de réparation des cassures double-brin avec l’apparition des chromosomes dicentriques sporadiques et une fréquence importante des micronoyaux avec la formation des ponts anaphasiques.La deuxième partie de cette thèse a été consacrée à l’étude des mécanismes de maintenance des télomères dans les ganglions tumoraux du lymphome de Hodgkin (50 patients) comme dans les lignées tumorales. Nous avons montré qu’il existe une cohabitation entre les deux mécanismes importants de maintenance des télomères, l’activation de la télomérase d’une part et le mécanisme ALT (alternative lengthening of telomeres) d’autre part. Nous avons identifié la présence de petites cellules dans les ganglions hodgkiniens comme dans les lignées tumorales avec une forte activité de la télomérase par contre la cellule de Reed Sternberg est caractérisée par un profil ALT avec la présence des corps PML et une très faible activité de télomérase. La fréquence des cellules télomérase ou ALT varie d’un ganglion à un autre et d’une lignée à une autre. Un drastique raccourcissement télomérique a été observé dans les cellules exprimant la télomérase. Pour les cellules ALT, une grande hétérogénéité de la taille des télomères ainsi que la présence des chromosomes dicentriques sporadiques ont été détectées. Le suivi des patients à long terme pendant 10 ans, nous a permis d’établir une corrélation entre le profil ALT et la survenue de mortalités et de morbidités. De plus, l’étude de la radiosensibilité des lignées tumorales a montré que les lignées ALT sont plus résistantes que les lignées télomérases.La troisième partie de cette thèse a été consacrée à la validation de ces deux concepts d’instabilité chromosomique via l’instabilité télomérique et à celle des mécanismes de maintenance des télomères, en utilisant un modèle de lymphome de Hodgkin établi dans le laboratoire à partir de la lignée L428.Ces données auront une retombée clinique importante non seulement dans la compréhension et le traitement des lymphomes de Hodgkin mais aussi dans d’autres pathologies malignes. / The study of Hodgkin lymphoma (HL), with its unique microenvironment and long clinical outcomes, has provided exceptional insights into several areas of tumour biology. Findings in HL have not only improved our understanding of human carcinogenesis, but have also pioneered its translation into the clinic.Tumoral cells in HL, called Hodgkin and reed Sternberg cells (HRS), are characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations, complex chromosomal rearrangements, and aneuploidy. Moreover, the scarcity of HRS cells and the resulting technical problems of their in situ characterization, the primary cytogenetic events and the clonality of these possible aberrations has been a matter of debate in the past. As a consequence, a few accepted and established HL cell lines are widely used in the majority of research projects conducted worldwide.In this thesis, first we have first investigated the possible mechanisms underlying genomic instability including microsatellite and chromosomal instability in HL cell lines. We provide the first evidence that the genomic instability observed in HL is related to microsatellite instability and chromosomal instability related to two major mechanisms: first, telomere fusion leading to dicentric chromosomes formation and breakage/fusion/bridge (B/F/B) cycles involving the repeated fusion and breakage of chromosomes following the loss of telomeres in small cells associated with the lower expression of TRF2, as well as an elevated copy number of the Jak2 gene and the presence of nucleoplasmic bridges containing telomere and centromere sequences. The second mechanism is related to defective DNA repair via non homologous end-joining (NHEJ) repair with the presence of nucleoplasmic bridges without telomere or centromere sequences, accompanied by the micronucleus without centromere sequences and a higher frequency of sporadic dicentric chromosomes.The second part of this thesis has focused on investigating telomere maintenance mechanisms (TMMs) not only in HL cell lines but also in lymph nodes of HL patients. A telomerase-independent mechanism for TMM in HL has been proposed in the absence of detectable telomerase activity (TA) in some cases. The major finding of this work has been the demonstration of the presence of both telomerase and ALT mechanism in lymph nodes of HL patients as well as in HL cell lines. We have identified a subset of tumors with some small cells expressing telomerase and Reed Sternberg cells containing ALT-associated PML bodies. A significant correlation was observed between telomere length and TMMs. Drastic telomere shortening was observed in cells with telomerase expression and elevated heterogeneity of telomere length was found in ALT profile cells. Interestingly, complex chromosomal rearrangements, included sporadic dicentric formation, were observed in ALT profile cell lines. Interestingly, the relationship between TMMs and all-cause mortality and morbidity during 10 years of follow-up of HL patients using cox proportion hazard models demonstrated a poor clinical outcome for HL patients exhibiting primarily ALT mechanisms. Similarly, higher radiation sensitivity was observed for cell lines with high telomerase activity compared to cell lines with the ALT profile.

No description available.

The aim of the study was to investigate whether non-thermal levels of radiofrequency (RF) fields, characteristic of some mobile phones, might be directly genotoxic when applied in vitro to unstimulated G0 or stimulated human lymphocytes. Also, the study aimed to investigate the possibility that RF fields might act epipigenetically when combined with x-rays, by modifying their effect when applied in vitro to G0 lymphocytes. In addition, the possibility of RF fields inducing apoptosis in murine neuroblastoma (N2a) cells was also examined. G0 lymphocytes from 4 donors were exposed for a total of 24 h to a continuous or an intermittent RF signal. The signals were 935 MHz GSM (Global System for Mobile Communication) Basic, 1800 MHz GSM Basic, 935 MHz continuous wave (CW) carrier frequency, and 935 MHz GSM Talk. Stimulated lymphocytes were exposed for a total of 48 h to intermittent 1800 MHz RF signals that were GSM Basic or the carrier frequency only. The RF fields used for the 24 h exposure of N2a cells were all at 935 MHz and consisted of GSM Basic, GSM Talk and a CW signal. The chosen Specific energy Absorption values of the signals were either 1 or 2 W/kg. These values are near the upper limit of actual energy absorbed in localised tissue by a person from some mobile phones. The field was applied to G0 human lymphocytes either alone or combined with an exposure to 1 Gy x-rays given immediately before or after the RF field. A dose of 4 Gy x-rays was used as a positive control for apoptosis induction in N2a cells and in the study with stimulated lymphocytes no x-rays were used. The lymphocytes were assayed by several standard methods to demonstrate genotoxicity. Unstable chromosome aberrations (stimulated lymphocytes and those exposed in G0), sister chromatid exchanges (SCE) and cytokinesis blocked micronuclei (MN) (lymphocytes exposed in G0). In addition the SCE and MN assays allowed nuclear division indices (NDI) to be calculated as NDI defines the cell cycle progression of lymphocytes after PHA stimulation and how this might be affected by RF exposure. N2a cells were assessed by fluorescence microscopy for levels of apoptosis at a number of time points post RF field or x-ray exposure, between 0 and 48 h. Three independent assays that detect different stages of the apoptotic pathway were used, the Annexin V binding, caspase activation and in situ end labelling. By comparison with appropriate sham exposed samples no effect of RF fields alone could be found in G0 or PHA stimulated lymphocytes exposed in vitro. Also, RF fields did not modify any measured effects of x-rays either given before or after RF exposure. No statistically significant difference in apoptosis levels were observed between RF exposed and sham exposed N2a cells in either a proliferating or differentiated state for any assay at any time point post exposure.

by Jenney Yin-mei Tse. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 122-146). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Bik-Yu Hui. / "July 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 187-203). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

The performance of optical imaging systems relies on control of aberrations that can arise from limitations in the design, manufacture, or alignment. This dissertation addresses the form of aberrations that occur for misaligned reflective systems, such as telescopes. The relationship between a characteristic set of field-dependent aberrations and the misalignments that cause them is systematically explored. A comprehensive technique that quantifies field performance for a 5-mirror system is given, using Monte Carlo analysis to provide confidence levels of image quality as functions of manufacturing and alignment errors. This analysis is an example of the "forward problem"— determining optical performance of a system if the errors are assumed. The inverse problem — determining the state of alignment based on measurements of performance — is more difficult. The solution to the inverse problem for a multiple mirror system requires an understanding of the complex coupling between many degrees of freedom (tilt, decenter, despace, shape error) of the optical elements and field-dependent aberrations.This work builds on previous treatment of field dependent optical aberrations from Tessieres, Thompson, Shack, Buchroeder and others. A basis set of field-dependent aberrations orthogonal over both field and pupil are developed here and used to describe systems with misaligned and misshapen optics. This description allows complete representation of high order and non-linear effects. The functional form of aberrations that are characteristic of mirror tilt, shift, and deformation show some useful patterns that provide insight to the fundamental effects of misalignment.The use of singular value decomposition to create orthogonal combinations of the field dependent aberrations provides a powerful tool for evaluating a system and for estimating the state of alignment using wavefront measurements. The following optical systems are evaluated to investigate the linear coupling between misalignment and the resulting field dependent aberrations:* 2-mirror telescopes, evaluating well-understood effects for an axisymmetric system and developing the relationships for an unobscured system.* 4-mirror correctors for a spherical primary telescope.The tools and methods are applied to reflective optical systems for astronomical telescopes, but the methods are general and can be useful for any optical imaging system.

Quadratic pupils representing Gaussian apodization and defocus are expanded into Zernike polynomials. Combinations of the pupil expansion coefficients are used, in turn to expand the Optical Transfer Function into a novel set of basis functions.

Aberrations affect image quality of the eye away from the line of sight as well as along it. High amounts of lower order aberrations are found in the peripheral visual field and higher order aberrations change away from the centre of the visual field. Peripheral resolution is poorer than that in central vision, but peripheral vision is important for movement and detection tasks (for example driving) which are adversely affected by poor peripheral image quality. Any physiological process or intervention that affects axial image quality will affect peripheral image quality as well. The aim of this study was to investigate the effects of accommodation, myopia, age, and refractive interventions of orthokeratology, laser in situ keratomileusis and intraocular lens implantation on the peripheral aberrations of the eye. This is the first systematic investigation of peripheral aberrations in a variety of subject groups. Peripheral aberrations can be measured either by rotating a measuring instrument relative to the eye or rotating the eye relative to the instrument. I used the latter as it is much easier to do. To rule out effects of eye rotation on peripheral aberrations, I investigated the effects of eye rotation on axial and peripheral cycloplegic refraction using an open field autorefractor. For axial refraction, the subjects fixated at a target straight ahead, while their heads were rotated by ±30º with a compensatory eye rotation to view the target. For peripheral refraction, the subjects rotated their eyes to fixate on targets out to ±34° along the horizontal visual field, followed by measurements in which they rotated their heads such that the eyes stayed in the primary position relative to the head while fixating at the peripheral targets. Oblique viewing did not affect axial or peripheral refraction. Therefore it is not critical, within the range of viewing angles studied, if axial and peripheral refractions are measured with rotation of the eye relative to the instrument or rotation of the instrument relative to the eye. Peripheral aberrations were measured using a commercial Hartmann-Shack aberrometer. A number of hardware and software changes were made. The 1.4 mm range limiting aperture was replaced by a larger aperture (2.5 mm) to ensure all the light from peripheral parts of the pupil reached the instrument detector even when aberrations were high such as those occur in peripheral vision. The power of the super luminescent diode source was increased to improve detection of spots passing through the peripheral pupil. A beam splitter was placed between the subjects and the aberrometer, through which they viewed an array of targets on a wall or projected on a screen in a 6 row x 7 column matrix of points covering a visual field of 42 x 32. In peripheral vision, the pupil of the eye appears elliptical rather than circular; data were analysed off-line using custom software to determine peripheral aberrations. All analyses in the study were conducted for 5.0 mm pupils. Influence of accommodation on peripheral aberrations was investigated in young emmetropic subjects by presenting fixation targets at 25 cm and 3 m (4.0 D and 0.3 D accommodative demands, respectively). Increase in accommodation did not affect the patterns of any aberrations across the field, but there was overall negative shift in spherical aberration across the visual field of 0.10 ± 0.01m. Subsequent studies were conducted with the targets at a 1.2 m distance. Young emmetropes, young myopes and older emmetropes exhibited similar patterns of astigmatism and coma across the visual field. However, the rate of change of coma across the field was higher in young myopes than young emmetropes and was highest in older emmetropes amongst the three groups. Spherical aberration showed an overall decrease in myopes and increase in older emmetropes across the field, as compared to young emmetropes. Orthokeratology, spherical IOL implantation and LASIK altered peripheral higher order aberrations considerably, especially spherical aberration. Spherical IOL implantation resulted in an overall increase in spherical aberration across the field. Orthokeratology and LASIK reversed the direction of change in coma across the field. Orthokeratology corrected peripheral relative hypermetropia through correcting myopia in the central visual field. Theoretical ray tracing demonstrated that changes in aberrations due to orthokeratology and LASIK can be explained by the induced changes in radius of curvature and asphericity of the cornea. This investigation has shown that peripheral aberrations can be measured with reasonable accuracy with eye rotation relative to the instrument. Peripheral aberrations are affected by accommodation, myopia, age, orthokeratology, spherical intraocular lens implantation and laser in situ keratomileusis. These factors affect the magnitudes and patterns of most aberrations considerably (especially coma and spherical aberration) across the studied visual field. The changes in aberrations across the field may influence peripheral detection and motion perception. However, further research is required to investigate how the changes in aberrations influence peripheral detection and motion perception and consequently peripheral vision task performance.

This work does not limit itself to its title and touches on a number of related topics beyond it. Starting with the title, Polarization Aberrations of Optical Coatings, the immediate question that comes to mind is: what coatings? All coatings? Not all coatings, but just enough that a third person could take this information and apply it anywhere: to all coatings. The computational work-flow required to break-down the aberrations caused by polarizing events (3D vector forms of reflection and refraction) in dielectric and absorbing materials and for thick and thin films is presented. Therefore, it is completely general and of interest to the wide optics community. The example system is a Ritchey-Chrétien telescope. It looks very similar to a Cassegrain, but it is not. It has hyperbolic surfaces, which allows for more optical aberration corrections. A few modern systems that use this configuration are the Hubble Space Telescope and the Keck telescopes. This particular system is a follow-up on this publication, where an example Cassegrain with aluminum coatings is characterized, and I was asked to simply evaluate it at another wavelength. To my surprise, I found a number of issues which lead me to write a completely new, one-of-its-kind 3D polarization ray-tracing code. It can do purely geometrical ray-tracing with add-on the polarization analysis capability, and more importantly: it keeps your data at your fingertips while offering all the outstanding facilities of Mathematica. The ray-tracing code and its extensive library, which can do several advanced computations, is documented in the appendix. The coatings of the Ritchey-Chrétien induce a number of aberrations, primarily, but not limited to: tilt, defocus, astigmatism, and coma. I found those forms to exist in both aluminum and with a reflectance-enhancing dielectric quarter-wave multilayer coating over aluminum. The thickness of the film stack varies as function of position to present a quarter-wave of optical thickness to oblique rays. Most commercial optical software that I know cannot compute this. And the results are impressive: the scalar transmission, which is a measure of ray efficiency, was raised from 78% to 95%. This means that only 5% of the incident light is lost, assuming ideal coating interfaces. This is very advantageous, considering the application: coronagraphs for exoplanet detection. Exoplanets are very far away, and therefore efficient use of light is essential. I also created a ray! I call it Huygens' twin ray. It is credited to Christiaan Huygens, who postulated that points on a wavefront can be considered as a sources of secondary spherical wavelets. This concept normally belongs to physical optics. The twin ray is emitted from the exact same object point but traced in a slightly different direction, which can be assumed by invoking Huygens's principle, and defined in a special way that consistently prevents vignetting. This requires high-precision ray-tracing, which is introduced along with this thesis work as part of the appendix. The application of this concept is exemplified in finding the exit pupil of the Ritchey-Chrétien telescope. It can be modified to work in a plurality of cases and find the precise image location in three-dimensions, making it completely general and useful. Mastering the ray-tracing documented here depends on how much optics the user knows, but tracing a single ray is something that can be learned in minutes. I welcome you to freely use it and make it your own. If your goal is to learn to ray-trace in Mathematica, the reader is directed to the appendix, especially to the four-port polarimeter example, as it is a 3D system that contains both reflection and refraction through thin films, thick films, retarders, and a single surface is traced at a time!

Standard adaptive optics systems measure the aberrations in the wavefronts of a beacon guide star caused by atmospheric turbulence, which limits the corrected field of view to the isoplanatic patch, the solid angle over which the optical aberration is roughly constant. For imaging systems that require a corrected field of view larger than the isoplanatic angle, a three-dimensional estimate of the aberration is required. We are developing a wide-field imaging Shack-Hartmann wavefront sensor (WFS) that will characterize turbulence over a large field of view tens of times the size of the isoplanatic angle. The technique will find application in horizontal and downward looking remote sensing scenarios where high resolution imaging through extended atmospheric turbulence is required. The laboratory prototype system consists of a scene generator, turbulence simulator, a Shack Hartman WFS arm, and an imaging arm. The system has a high intrinsic Strehl ratio, is telecentric, and diffraction limited. We present preliminary data and analysis from the system.