Aboriginal Glass Artefacts of the Sydney Region

Aboriginal glass artefacts (AGAs) have become the ‘type fossil’ for recognizing post-contact sites in countries with colonial pasts. Whether such reliance on AGAs is a valid development is contentious as the identification of these artefacts is ambiguous. This uncertainty is amplified in densely populated urban environments such as Sydney. This thesis addresses the identification of these artefacts within this region. Technological characteristics of Sydney’s AGAs and methodological issues in the recording of these artefacts have been analysed. A review of the patterns within this data has revealed how the identification issue has been managed in the past and how it may be improved. A review and evaluation of previous ‘criteria for identification’ has also revealed a refined approach to the identification and categorization of AGAs within Sydney and beyond. Also, cross-cultural interactions have been characterized as affected by the unique and diverse nature of the moving frontier in this region

Insight into mucinous colorectal carcinoma: clues from etiology

The prognostic impact of mucinous carcinoma (MC) in colorectal cancer (CRC) has been subject to debate ever since the introduction of the classification of tumors according to their histological differentiation. MC is a distinct clinical and pathological entity within the spectrum of CRC and accounts for approximately 10-15 % of cases. Factors involved in MC development have not been completely understood, but clinical observations may lead to a better insight into the etiology of MC. In this article, we provide an in-depth review of the literature regarding etiological aspects of MC. We show that there are worldwide differences in the prevalence of MC, with low rates in Asian countries and higher rates in the western world. Moreover, MC is more commonly diagnosed in patients suffering from inflammatory bowel diseases or Lynch syndrome and an increased rate of MC is observed in patients with radiotherapy-induced CRCs. These findings are suggestive of a different oncogenic development. Identification of conditions that are associated with MC generates insight into the etiological pathways leading to the development of this special subtype

Insight into mucinous colorectal carcinoma: clues from etiology

Contains fulltext : 138320pub.pdf (publisher's version ) (Closed access)The prognostic impact of mucinous carcinoma (MC) in colorectal cancer (CRC) has been subject to debate ever since the introduction of the classification of tumors according to their histological differentiation. MC is a distinct clinical and pathological entity within the spectrum of CRC and accounts for approximately 10-15 % of cases. Factors involved in MC development have not been completely understood, but clinical observations may lead to a better insight into the etiology of MC. In this article, we provide an in-depth review of the literature regarding etiological aspects of MC. We show that there are worldwide differences in the prevalence of MC, with low rates in Asian countries and higher rates in the western world. Moreover, MC is more commonly diagnosed in patients suffering from inflammatory bowel diseases or Lynch syndrome and an increased rate of MC is observed in patients with radiotherapy-induced CRCs. These findings are suggestive of a different oncogenic development. Identification of conditions that are associated with MC generates insight into the etiological pathways leading to the development of this special subtype

Does pelvic radiation increase rectal cancer incidence? - A systematic review and meta-analysis

Contains fulltext : 195651.pdf (publisher's version ) (Open Access)BACKGROUND: One of the late complications associated with radiation therapy (RT) is a possible increased risk of second cancer. In this systematic review, we analysed the incidence of rectal cancer following primary pelvic cancer irradiation. METHODS: A literature search was conducted using the PubMed and EMBASE libraries. Original articles that reported on secondary rectal cancer after previous RT for a primary pelvic cancer were included. Sensitivity analyses were performed by correcting for low number of events, high risk of bias, and outlying results. RESULTS: A total of 5171 citations were identified during the literature search, 23 studies were included in the meta-analyses after screening. A pooled analysis, irrespective of primary tumour location, showed an increased risk for rectal cancer following RT (N=403.243) compared with non-irradiated patients (N=615.530) with a relative risk (RR) of 1.43 (95% confidence interval [CI] 1.18-1.72). Organ specific meta-analysis showed an increased risk for rectal cancer after RT for prostate (RR 1.36, 95%CI 1.10-1.67) and cervical cancer (RR 1.61, 95% CI 1.10-2.35). No relation was seen in ovarian cancer patients. The modality of RT did not influence the incidence of rectal cancer. CONCLUSIONS: This review demonstrates an increased risk for second primary rectal cancer in patients who received RT to the pelvic region. This increased risk was modest and could not be confirmed for all primary pelvic cancer sites. The present study does not provide data to change guidelines for surveillance for rectal cancer in previously irradiated patients

Protamine-stabilized RNA as an ex vivo stimulant of primary human dendritic cell subsets

Contains fulltext : 152626.pdf (Publisher’s version ) (Open Access)Dendritic cells (DCs) are key in connecting innate and adaptive immunity. Their potential in inducing specific immune responses has made them interesting targets for immunotherapeutic approaches. Our research group was the first to exploit the naturally occurring myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in therapeutic vaccination trials against melanoma. To develop primary DC subsets as an optimal vaccine, the identification of a clinically applicable adjuvant activating both subsets is required. Although the expression of pathogen recognition receptors differs distinctly between the DC subsets, both pDCs and mDCs can respond to single-stranded RNA (ssRNA) via Toll-like receptors 7 and 8, respectively. Since ssRNA is easily degraded by RNases, we stabilized anionic RNA by complexing it with the positively charged protein protamine. This leads to the formation of protamine-RNA complexes with varying features depending on ionic content. We subsequently investigated the immunostimulatory effect of complexes that formed various salt concentrations on purified DC subsets. Both mDCs and pDCs upregulated maturation markers and produced pro-inflammatory cytokines in a dose-dependent way to the protamine-RNA complexes. This was dependent on endosomal acidification and correlated partly with the uptake of protamine-RNA complexes. Furthermore, both DC subsets induced T cell proliferation and IFN gamma secretion in a beneficial ratio to IL-10. These results indicate that protamine-RNA complexes can be used to stimulate human mDC and pDC ex vivo for use in immunotherapeutic settings

Human blood myeloid and plasmacytoid dendritic cells cross activate each other and synergize in inducing NK cell cytotoxicity

Human blood dendritic cells (DCs) hold great potential for use in anticancer immunotherapies. CD1c+ myeloid DCs and plasmacytoid DCs (pDCs) have been successfully utilized in clinical vaccination trials against melanoma. We hypothesize that combining both DC subsets in a single vaccine can further improve vaccine efficacy. Here, we have determined the potential synergy between the two subsets in vitro on the level of maturation, cytokine expression, and effector cell induction. Toll-like receptor (TLR) stimulation of CD1c+ DCs induced cross-activation of immature pDCs and vice versa. When both subsets were stimulated together using TLR agonists, CD86 expression on pDCs was increased and higher levels of interferon (IFN)-alpha were produced by DC co-cultures. Although the two subsets did not display any synergistic effect on naive CD4+ and CD8+ T cell polarization, CD1c+ DCs and pDCs were able to complement each other's induction of other immune effector cells. The mere presence of pDCs in DC co-cultures promoted plasma cell differentiation from activated autologous B cells. Similarly, CD1c+ DCs, alone or in co-cultures, induced high levels of IFN-gamma from allogeneic peripheral blood lymphocytes or activated autologous natural killer (NK) cells. Both CD1c+ DCs and pDCs could enhance NK cell cytotoxicity, and interestingly DC co-cultures further enhanced NK cell-mediated killing of an NK-resistant tumor cell line. These results indicate that co-application of human blood DC subsets could render DC-based anticancer vaccines more efficacious

Naturally produced type I IFNs enhance human myeloid dendritic cell maturation and IL-12p70 production and mediate elevated effector functions in innate and adaptive immune cells

Contains fulltext : 196642.pdf (Publisher’s version ) (Open Access)There has recently been a paradigm shift in the field of dendritic cell (DC)-based immunotherapy, where several clinical studies have confirmed the feasibility and advantageousness of using directly isolated human blood-derived DCs over in vitro differentiated subsets. There are two major DC subsets found in blood; plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), and both have been tested clinically. CD1c(+) mDCs are highly efficient antigen-presenting cells that have the ability to secrete IL-12p70, while pDCs are professional IFN-alpha-secreting cells that are shown to induce innate immune responses in melanoma patients. Hence, combining mDCs and pDCs poses as an attractive, multi-functional vaccine approach. However, type I IFNs have been reported to inhibit IL-12p70 production and mDC-induced T-cell activation. In this study, we investigate the effect of IFN-alpha on mDC maturation and function. We demonstrate that both recombinant IFN-alpha and activated pDCs strongly enhance mDC maturation and increase IL-12p70 production. Co-cultured mDCs and pDCs additionally have beneficial effect on NK and NKT-cell activation and also enhances IFN-gamma production by allogeneic T cells. In contrast, the presence of type I IFNs reduces the proliferative T-cell response. The mere presence of a small fraction of activated pDCs is sufficient for these effects and the required ratio between the subsets is non-stringent. Taken together, these results support the usage of mDCs and pDCs combined into one immunotherapeutic vaccine with broad immunostimulatory features