Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8+CD4+ T cells : evidence from myeloma-bearing mouse model

The graft-versus-myeloma (GVM) effect represents a powerful form of immune attack exerted by alloreactive T cells against multiple myeloma cells, which leads to clinical responses in multiple myeloma transplant recipients. Whether myeloma cells are themselves able to induce alloreactive T cells capable of the GVM effect is not defined. Using adoptive transfer of T naive cells into myeloma-bearing mice (established by transplantation of human RPMI8226-TGL myeloma cells into CD122(+) cell-depleted NOD/SCID hosts), we found that myeloma cells induced alloreactive T cells that suppressed myeloma growth and prolonged survival of T cell recipients. Myeloma-induced alloreactive T cells arising in the myeloma-infiltrated bones exerted cytotoxic activity against resident myeloma cells, but limited activity against control myeloma cells obtained from myeloma-bearing mice that did not receive T naive cells. These myeloma-induced alloreactive T cells were derived through multiple CD8(+) T cell divisions and enriched in double-positive (DP) T cells coexpressing the CD8alphaalpha and CD4 coreceptors. MHC class I expression on myeloma cells and contact with T cells were required for CD8(+) T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-gamma and/or perforin compared with single-positive CD8(+) T cells, acquired the capacity to degranulate as measured by CD107 expression, and contributed to an elevated perforin level seen in the myeloma-infiltrated bones. These observations suggest that myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones are enriched with DP-T cells equipped with cytotoxic effector functions that are likely to be involved in the GVM effect.

Visible-light-induced selective photocatalytic oxidation of benzylamine into imine over supported Ag/AgI photocatalysts

Titanate nanotubes (TNT) supported AgI nanoparticles were prepared by a two-step method: the deposition of Ag2O on titanate nanotubes from AgNO3 solution and the subsequent I-adsorption process from NaI solution. It is found that the supported AgI samples exhibited excellent photoactivity for the selective oxidation of benzylamine to the corresponding imine under visible light illumination and the photocatalyst can be used for many times without apparent activity loss. X-ray diffraction studies, transmission electron microscopy, diffuse reflectance UV-Vis spectroscopy and nitrogen adsorption measurements were used for the characterization of the as-prepared and recycled AgI samples. It is found that under visible light irradiation, AgI partially decomposed to produce Ag/AgI nanostructure and thus stabilized. The photoactivity of supported Ag/AgI for the selective oxidation of benzylamine was studied in terms of the light intensity, wavelength, temperature and substituent. It is proposed that the formation of plasmonic Ag nanoparticles should be responsible for the high activity and selectivity.

Differential subcellular and extracellular localisations of proteins required for insulin-like growth factor- and extracellular matrix-induced signalling events in breast cancer progression

Background: Cancer metastasis is the main contributor to breast cancer fatalities as women with the metastatic disease have poorer survival outcomes than women with localised breast cancers. There is an urgent need to develop appropriate prognostic methods to stratify patients based on the propensities of their cancers to metastasise. The insulin-like growth factor (IGF)-I:IGF binding protein (IGFBP):vitronectin complexes have been shown to stimulate changes in gene expression favouring increased breast cancer cell survival and a migratory phenotype. We therefore investigated the prognostic potential of these IGF- and extracellular matrix (ECM) interaction-induced proteins in the early identification of breast cancers with a propensity to metastasise using patient-derived tissue microarrays. Methods: Semiquantitative immunohistochemistry analyses were performed to compare the extracellular and subcellular distribution of IGF- and ECM-induced signalling proteins among matched normal, primary cancer and metastatic cancer formalin-fixed paraffin-embedded breast tissue samples. Results: The IGF- and ECM-induced signalling proteins were differentially expressed between subcellular and extracellular localisations. Vitronectin and IGFBP-5 immunoreactivity was lower while β1 integrin immunoreactivity was higher in the stroma surrounding metastatic cancer tissues, as compared to normal breast and primary cancer stromal tissues. Similarly, immunoreactive stratifin was found to be increased in the stroma of primary as well as metastatic breast tissues. Immunoreactive fibronectin and β1 integrin was found to be highly expressed at the leading edge of tumours. Based on the immunoreactivity it was apparent that the cell signalling proteins AKT1 and ERK1/2 shuffled from the nucleus to the cytoplasm with tumour progression. Conclusion: This is the first in-depth, compartmentalised analysis of the distribution of IGF- and ECM-induced signalling proteins in metastatic breast cancers. This study has provided insights into the changing pattern of cellular localisation and expression of IGF- and ECM-induced signalling proteins in different stages of breast cancer. The differential distribution of these biomarkers could provide important prognostic and predictive indicators that may assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy.

Artemisinin-induced parasite dormancy : a plausible mechanism for treatment failure

Background Artemisinin-combination therapy is a highly effective treatment for uncomplicated falciparum malaria but parasite recrudescence has been commonly reported following artemisinin (ART) monotherapy. The dormancy recovery hypothesis has been proposed to explain this phenomenon, which is different from the slower parasite clearance times reported as the first evidence of the development of ART resistance. Methods In this study, an existing P. falciparum infection model is modified to incorporate the hypothesis of dormancy. Published in vitro data describing the characteristics of dormant parasites is used to explore whether dormancy alone could be responsible for the high recrudescence rates observed in field studies using monotherapy. Several treatment regimens and dormancy rates were simulated to investigate the rate of clinical and parasitological failure following treatment. Results The model output indicates that following a single treatment with ART parasitological and clinical failures occur in up to 77% and 67% of simulations, respectively. These rates rapidly decline with repeated treatment and are sensitive to the assumed dormancy rate. The simulated parasitological and clinical treatment failure rates after 3 and 7 days of treatment are comparable to those reported from several field trials. Conclusions Although further studies are required to confirm dormancy in vivo, this theoretical study adds support for the hypothesis, highlighting the potential role of this parasite sub-population in treatment failure following monotherapy and reinforcing the importance of using ART in combination with other anti-malarials.

Artemisinin induced dormancy in Plasmodium falciparum : duration, recovery rates and implications in treatment failure

Background Despite the remarkable activity of artemisinin and its derivatives, monotherapy with these agents has been associated with high rates of recrudescence. The temporary arrest of the growth of ring-stage parasites (dormancy) after exposure to artemisinin drugs provides a plausible explanation for this phenomenon. Methods Ring-stage parasites of several Plasmodium falciparum lines were exposed to different doses of dihydroartemisinin (DHA) alone or in combination with mefloquine. For each regime, the proportion of recovering parasites was determined daily for 20 days. Results Parasite development was abruptly arrested after a single exposure to DHA, with some parasites being dormant for up to 20 days. Approximately 50% of dormant parasites recovered to resume growth within the first 9 days. The overall proportion of parasites recovering was dose dependent, with recovery rates ranging from 0.044% to 1.313%. Repeated treatment with DHA or with DHA in combination with mefloquine led to a delay in recovery and an ∼10-fold reduction in total recovery. Strains with different genetic backgrounds appeared to vary in their capacity to recover. Conclusions These results imply that artemisinin-induced arrest of growth occurs readily in laboratory-treated parasites and may be a key factor in P. falciparum malaria treatment failure.

E-mail in the workplace : the role of stress appraisals and normative response pressure in the relationship between email stressors and employee strain

In many organizations, e-mail is an effective and dominant workplace application tool; however, research identifying its role as a potential workplace stressor remains limited. Utilizing the Transactional Model of Stress (Lazarus & Folkman, 1984), 215 full-time administrative and academic staff at a university were surveyed about workplace e-mail. The aim was to study the effects of potential e-mail stressors on emotional exhaustion as mediated and moderated by person and situation variables. Results indicated that 2 distinct e-mail stressors—high quantity and poor quality (in terms of high emotionality and ambiguity) of workplace e-mail—were associated both with stress appraisals (e-mail overload and e-mail uncertainty) and with emotional exhaustion. Furthermore, the effects of the 2 e-mail stressors on emotional exhaustion were mediated by appraised e-mail overload. Perceived normative response pressure—a relevant aspect of the specific work environment—added to the explanation of emotional exhaustion and accentuated the positive effect of e-mail ambiguity on emotional exhaustion, although effects involving normative response pressure were not explained by the stress appraisals.

Energy price-induced and exogenous technological change : Assessing the economic and environmental outcomes

In this paper, we distinguish between factor/output substitution and shifts in the production technology frontier. Our model includes the by-products of carbon dioxide and sulfur dioxide emissions where the function requires the simultaneous expansion of good outputs and reductions in emissions. We estimate a directional output distance function for 80 countries over the period 1971-2000 to measure the exogenous and oil price-induced technological change. On average, we find substantial oil price-induced technological progress at the world level when long-term oil prices are rising, although the growth rate is more volatile in developed countries than in developing countries. The results also show that developed countries experience higher exogenous technological progress in comparison with developing countries, and the gap between the two has increased during the period of our study.

Trade-induced technological change : analyzing economic and environmental outcomes

We analyze how changes in trade openness are related to induced technological innovations that are not only GDP increasing but also pollution saving. Our model includes by-products of carbon dioxide and sulfur dioxide emissions. We estimate a directional distance function for 76 countries over the period 1963-2000 to measure exogenous and trade-induced technological change. On average, we find substantial trade-induced technological progress, and its magnitude is about one third of the overall technological change. The trade-induced technological changes, however, are GDP reducing and pollution increasing. Empirically, we find that increased trade openness correlates to increased pollution.

A novel method of Fiber Bragg Grating (FBG) strain modulation and its application in FBG accelerometers

This thesis has systemically investigated the possibility of improving one type of optical fiber sensors by using a novel mechanism. Many parameters of the sensor have been improved, and one outcome of this innovation is that civil structures, such as bridges and high-rise buildings, may be operated more safely and used longer.

Heat strain evaluation of overt and covert body armour in a hot and humid environment

The aim of this study was to elucidate the thermophysiological effects of wearing lightweight non-military overt and covert personal body armour (PBA) in a hot and humid environment. Eight healthy males walked on a treadmill for 120 min at 22% of their heart rate reserve in a climate chamber simulating 31 °C (60%RH) wearing either no armour (control), overt or covert PBA in addition to a security guard uniform, in a randomised controlled crossover design. No significant difference between conditions at the end of each trial was observed in core temperature, heart rate or skin temperature (P > 0.05). Covert PBA produced a significantly greater amount of body mass change (−1.81 ± 0.44%) compared to control (−1.07 ± 0.38%, P = 0.009) and overt conditions (−1.27 ± 0.44%, P = 0.025). Although a greater change in body mass was observed after the covert PBA trial; based on the physiological outcome measures recorded, the heat strain encountered while wearing lightweight, non-military overt or covert PBA was negligible compared to no PBA. Practitioner summary The wearing of bullet proof vests or body armour is a requirement of personnel engaged in a wide range of occupations including police, security, customs and even journalists in theatres of war. This randomised controlled crossover study is the first to examine the thermophysiological effects of wearing lightweight non-military overt and covert personal body armour (PBA) in a hot and humid environment. We conclude that the heat strain encountered while wearing both overt and covert lightweight, non-military PBA was negligible compared to no PBA.

A tissue-engineered humanised xenograft model of human breast cancer-induced bone metastasis and bone colonisation

This thesis focuses on the development of a humanised mouse model to investigate human breast cancer metastasis to bone, an incurable disease presenting a major medical challenge in our society. The method is based on tissue-engineered constructs with human cells that generate a human bone-like organ within mice. This novel platform is further applied to mimic human-specific mechanisms of breast cancer metastasis and growth in human bone, and in particular the role of specific cell adhesion molecules in this process is closely investigated.