Proteomic Identification of Interleukin-2 Therapy Response in Metastatic Renal Cell Cancer

Introduction—To detect a predictive protein profile that distinguishes between IL-2 therapy responders and non-responders among metastatic RCC patients we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI TOF-MS). Materials and Methods—Protein extracts of 56 metastatic clear cell RCC patients obtained from radical nephrectomy specimens and prior to IL-2 therapy were applied to protein chip arrays of different chromatographic properties and analyzed using SELDI TOF-MS. A class prediction algorithm was applied to identify a subset of protein peaks whose expression values were associated with IL-2 response status. Multivariate analysis was performed to assess the association between the proteomic profile and the IL-2 response status controlling for the effect of lymphadenopathy. Results—From a total of 513 protein peaks we discovered a predictor set of 11 peaks that performed optimally for predicting IL-2 response status (86 % accuracy, Fisher’s p\u3c0.004, permutation p\u3c0.01). The results were validated on an independent data set with an overall accuracy of 72% (p \u3c 0.05, permutation p\u3c0.01). On multivariate analysis the proteomic profile was significantly associated with IL-2 response when corrected for lymph node status (p\u3c 0.04). Conclusions—We have identified and validated a proteomic pattern that is an independent predictor of IL-2 response. The ability to predict the probability of IL-2 response could permit targeted selection of patients most likely to respond to IL-2, while avoiding unwanted toxicities in patients less likely to respond. This proteomic predictor has the potential to significantly aid clinicians in the decision making of appropriate therapy for metastatic RCC patients

Practising social justice: Community organisations, what matters and what counts

This thesis investigates the situated knowing-in-practice of locally-based community organisations, and studies how this practice knowledge is translated and contested in inter-organisational relations in the community services field of practices. Despite participation in government-led consultation processes, community organisations express frustration that the resulting policies and plans inadequately take account of the contributions from their practice knowledge. The funding of locally-based community organisations is gradually diminishing in real terms and in the competitive tendering environment, large nationally-based organisations often attract the new funding sources. The concern of locally-based community organisations is that the apparent lack of understanding of their distinctive practice knowing is threatening their capacity to improve the well-being of local people and their communities. In this study, I work with practitioners, service participants and management committee members to present an account of their knowing-in-practice, its character and conditions of efficacy; and then investigate what happens when this local practice knowledge is translated into results-based accountability (RBA) planning with diverse organisations and institutions. This thesis analyses three points of observation: knowing in a community of practitioners; knowing in a community organisation and knowing in the community services field of practices. In choosing these points of observation, the inquiry explores some of the relations and intra-actions from the single organisation to the institutional at a time when state government bureaucracy has mandated that community organisations implement RBA to articulate outcomes that can be measured by performance indicators. A feminist, performative, relational practice-based approach employs participatory action research to achieve an enabling research experience for the participants. It aims to intervene strategically to enhance recognition of the distinctive contributions of community organisations’ practice knowledge. This thesis reconfigures understandings of the roles, contributions and accountabilities of locally-based community organisations. Observations of situated practices together with the accounts of workers and service participants demonstrate how community organisations facilitate service participants’ struggles over social justice. A new topology for rethinking social justice as processual and practice-based is developed. It demonstrates how these struggles are a dynamic complex of iteratively-enfolded practices of respect and recognition, redistribution and distributive justice, representation and participation, belonging and inclusion. The focus on the practising of social justice in this thesis offers an alternative to the neo-liberal discourse that positions community organisations as sub-contractors accountable to government for delivering measurable outputs, outcomes and efficiencies in specified service provision contracts. The study shows how knowing-in-practice in locally-based community organisations contests the representational conception of knowledge inextricably entangled with accountability and performance measurement apparatus such as RBA. Further, it suggests that practitioner and service participant contributions are marginalised and diminished in RBA through the privileging of knowledge that takes an ‘expert’, quantifiable and calculative form. Thus crucially, harnessing local practice knowing requires re-imagining and enacting knowledge spaces that assemble and take seriously all relevant stakeholder perspectives, diverse knowledges and methods

Joint association of polymorphism of the FGFR4 gene and mutation TP53 gene with bladder cancer prognosis

The impact of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism on bladder cancer is unknown. We found no clear correlations between the FGFR4 genotype and risk of bladder cancer or pathological parameters. Neither the polymorphism nor TP53 mutation status was an independent predictor of prognosis, but they might act jointly on the disease-specific survival of patients

Salvage Cryotherapy for Radiation-Recurrent Prostate Cancer: Outcomes and Complications

Potentially curative salvage options for radio-recurrent prostate cancer include prostatectomy, brachytherapy, high-intensity focused ultrasound, and cryotherapy. Salvage cryoablation technology, surgical technique, oncologic outcomes, and complication rates have improved dramatically over the past few decades, shifting this treatment modality from investigational status to an established therapeutic option. In this review, we focus on the most up-to-date oncologic and functional outcomes, as well as complications of salvage cryotherapy for radiation-recurrent prostate cancer

Expansion and Characterization of Human Melanoma Tumor-Infiltrating Lymphocytes (TILs)

Various immunotherapeutic strategies for cancer are aimed at augmenting the T cell response against tumor cells. Adoptive cell therapy (ACT), where T cells are manipulated ex vivo and subsequently re-infused in an autologous manner, has been performed using T cells from various sources. Some of the highest clinical response rates for metastatic melanoma have been reported in trials using tumor-infiltrating lymphocytes (TILs). These protocols still have room for improvement and furthermore are currently only performed at a limited number of institutions. The goal of this work was to develop TILs as a therapeutic product at our institution.TILs from 40 melanoma tissue specimens were expanded and characterized. Under optimized culture conditions, 72% of specimens yielded rapidly proliferating TILs as defined as at least one culture reaching ≥3×10(7) TILs within 4 weeks. Flow cytometric analyses showed that cultures were predominantly CD3+ T cells, with highly variable CD4+:CD8+ T cell ratios. In total, 148 independent bulk TIL cultures were assayed for tumor reactivity. Thirty-four percent (50/148) exhibited tumor reactivity based on IFN-γ production and/or cytotoxic activity. Thirteen percent (19/148) showed specific cytotoxic activity but not IFN-γ production and only 1% (2/148) showed specific IFN-γ production but not cytotoxic activity. Further expansion of TILs using a 14-day "rapid expansion protocol" (REP) is required to induce a 500- to 2000-fold expansion of TILs in order to generate sufficient numbers of cells for current ACT protocols. Thirty-eight consecutive test REPs were performed with an average 1865-fold expansion (+/- 1034-fold) after 14 days.TILs generally expanded efficiently and tumor reactivity could be detected in vitro. These preclinical data from melanoma TILs lay the groundwork for clinical trials of ACT

The autocrine role of tumor necrosis factor in the proliferation and functional differentiation of human lymphokine-activated T killer cells (T-LAK) in vitro

The autocrine role of tumor necrosis factor alpha (TNF) in the proliferation and functional differentiation of human lymphokine-activated T-killer cells (T-LAK) in vitro was investigated. Human peripheral blood lymphocytes initially stimulated with IL-2 and phytohemagglutinin-P (PHA) for 48 h will proliferate for long periods in vitro in the presence of IL-2. These T-LAK cells have been shown to be 95% CD3 positive. Employing ELISA techniques, greater than 500 pg/ml of TNF was found to be released in the supernatants of these cells during the first 5 days of culture. However, the levels dropped to 100-200 pg/ml by days 7-10. T-LAK cells grown from days 7 to 10 in the presence of IL-2 and rabbit anti-TNF were significantly growth inhibited (up to 23%). The cytolytic activity of T-LAK cells grown from days 0 to 7 in the presence of anti-TNF was also decreased (up to 75%). Phenotypic analysis of these anti-TNF treated T-LAK cells revealed a decrease in CD8 expression (up to 12%) and increase in CD4 expression (up to 27%) when compared with control cells. The data suggest that TNF has a regulatory role in the growth and functional differentiation of these human T-LAK cells