The function and origin of the CD4+ T cell in the classical Hodgkin lymphoma microenvironment

PhDClassical Hodgkin lymphoma (CHL) is a germinal centre B cell malignancy where the bulk of the tumour comprises a non-clonal immune infiltrate enriched for CD4+ T cells. The role of these cells in the pathophysiology of CHL is poorly understood. Biomarkers predictive of clinical outcome in CHL are limited. This thesis examines microenvironment biomarkers with the goal of identifying the 10-20% of patients who are not cured by conventional therapy, and also investigates the function of the CD4+ T cell in CHL. The prognostic power of FOXP3, a marker of regulatory T cells, CD68, a macrophage marker and CD20, a B cell marker, is validated in a new patient cohort and for the first time CD68 and FOXP3 are combined in a statistically robust scoring system. The data presented challenge the assumption that the microenvironment is Th2-polarised or senescent and demonstrates relative over-expression of T-BET, a Th1 marker and under-expression of PD1, a marker of senescence/exhaustion, with little evidence for Th2 marker expression. A cytokine-enriched in vitro culture system was developed demonstrating superior proliferation and longevity of CHL-derived T cells compared to non-malignant tissue-derived controls. These cells sustain expression of markers associated with proliferation and longevity (e.g. CD27, CD28) and remain functional (express cytokines) for many weeks. A panel of CD4+ T cell-specific markers was determined capable of differentiating CHL-derived from non-malignant or non-Hodgkin lymphoma-derived CD4+ T cells, in which markers of central memory (CD62L and CCR7) and early activation (CD69) are over-represented and markers of senescence (CD57 and PD1) are under-represented. Cytokine profiles were found to resemble Th1 (expression of IL2, IFN- and TNF expression) rather than Th2 (IL4, IL13, IL21, IL10 and IL6) responses. The data presented confirm a new prognostic biomarker signature and show a Th1 rather than Th2-dominated microenvironment enriched for cytokine-secreting functional effector CD4+ T cells and long-lived, proliferative cells resembling central memory cells rather than hypoproliferative, anergic, non-functional T cells

New sub-millimeter limits on dust in the 55 Cancri planetary system

We present new, high-sensitivity sub-millimeter observations towards 55 Cancri, a nearby G8 star with one, or possibly two, known planetary companion(s). Our 850 $\mu$m map, obtained with the SCUBA instrument on the James Clerk Maxwell Telescope, shows three peaks of emission at the 2.5 mJy level in the vicinity of the star's position. However, the observed peaks are 25\arcsec--40\arcsec away from the star and a deep $R$-band optical image reveals faint point sources that coincide with two of the sub-millimeter peaks. Thus, we do not find evidence for dust emission spatially associated with 55 Cancri. The excess 60 $\mu$m emission detected with ISO may originate from one or more of the 850 $\mu$m peaks that we attribute to background sources. Our new results, together with the HST/NICMOS coronographic images in the near-infrared, place stringent limits on the amount of dust in this planetary system, and argue against the existence of a detectable circumstellar dust disk around 55 Cnc.Comment: 11 pages, 2 PostScript figures, to appear in The Astrophysical Journal Letter

Resolved Debris Discs Around A Stars in the Herschel DEBRIS Survey

The majority of debris discs discovered so far have only been detected through infrared excess emission above stellar photospheres. While disc properties can be inferred from unresolved photometry alone under various assumptions for the physical properties of dust grains, there is a degeneracy between disc radius and dust temperature that depends on the grain size distribution and optical properties. By resolving the disc we can measure the actual location of the dust. The launch of Herschel, with an angular resolution superior to previous far-infrared telescopes, allows us to spatially resolve more discs and locate the dust directly. Here we present the nine resolved discs around A stars between 20 and 40 pc observed by the DEBRIS survey. We use these data to investigate the disc radii by fitting narrow ring models to images at 70, 100 and 160 {\mu}m and by fitting blackbodies to full spectral energy distributions. We do this with the aim of finding an improved way of estimating disc radii for unresolved systems. The ratio between the resolved and blackbody radii varies between 1 and 2.5. This ratio is inversely correlated with luminosity and any remaining discrepancies are most likely explained by differences to the minimum size of grain in the size distribution or differences in composition. We find that three of the systems are well fit by a narrow ring, two systems are borderline cases and the other four likely require wider or multiple rings to fully explain the observations, reflecting the diversity of planetary systems.Comment: 19 pages, 13 figures, 6 tables. Accepted for publication in MNRA

Resolving debris discs in the far-infrared: early highlights from the DEBRIS survey

We present results from the earliest observations of DEBRIS, a Herschel Key Programme to conduct a volume- and flux-limited survey for debris discs in A-type through M-type stars. PACS images (from chop/nod or scan-mode observations) at 100 and 160 micron are presented toward two A-type stars and one F-type star: beta Leo, beta UMa and eta Corvi. All three stars are known disc hosts. Herschel spatially resolves the dust emission around all three stars (marginally, in the case of beta UMa), providing new information about discs as close as 11 pc with sizes comparable to that of the Solar System. We have combined these data with existing flux density measurements of the discs to refine the SEDs and derive estimates of the fractional luminosities, temperatures and radii of the discs.Comment: to be published in A&A, 5 pages, 2 color figure

Clopidogrel has no effect on D-dimer and thrombin-antithrombin III levels in patients with peripheral arterial disease undergoing peripheral percutaneous transluminal angioplasty

Objective: Coagulation activation markers are significantly elevated in patients with peripheral arterial disease compared with healthy controls. The more severe the disease, the higher the markers. Increased coagulation activation may contribute to the disease process and the risk of complications in patients with peripheral arterial disease, particularly after endovascular intervention. Animal studies have shown that clopidogrel significantly inhibits coagulation activation. The aim of this study was to determine whether combination of aspirin and clopidogrel affects thrombin-antithrombin III and D-dimer in patients with intermittent claudication undergoing angioplasty, compared with aspirin alone. Methods: This was a double blind, randomized placebo-controlled trial conducted in a vascular unit in a tertiary referral center. One hundred thirty-two patients with intermittent claudication were randomized to clopidogrel and aspirin or placebo and aspirin, with a loading dose 12 hours before endovascular intervention. D-dimer and thrombin-antithrom- bin III (TAT) levels were measured using enzyme-linked immunosorbent assay at baseline, 1 hour before, and 1 hour, 24 hours, and 30 days after intervention in 103 patients who underwent endovascular intervention. Results: There was a significant rise in D-dimer levels at 1 hour and 24 hours after angioplasty in both groups (placebo group: 63.69, 141.45, 122.18 ng/mL; clopidogrel group: 103.79, 159.95, 134.69 ng/mL), but no difference between the two groups (P .514). Similarly there was a significant rise in TAT levels at 1 hour after angioplasty in both groups (placebo group: 2.93, 6.16 g/L; clopidogrel group: 3.39, 5.27 g/L), with no significant difference between the two groups (P .746). Conclusion: Endovascular intervention results in a significant increase in TAT and D-dimer. The addition of clopidogrel to aspirin has no effect on TAT and D-dimer before or after endovascular intervention.peer-reviewe