99 research outputs found
kindspecifieke beenprothese voor de derde wereld
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Abstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers
No full textRecent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies.
As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017.
Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10.
©2017 American Association for Cancer Research
Abstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers
No full textAbstract
Recent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies.
As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017.
Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10.</jats:p
Cross-Cultural Meta-Analyses
No full textIn the enormous collection of cross-cultural data that have been published during the last few decades it is difficult to perceive patterns. There is a clear need for systematizing the vast amount of cross-cultural studies and for developing models that explain cross-cultural differences in psychology. Two methods of cross-cultural meta-analysis can be distinguished. First, the instrument-based method of comparing data for one instrument across countries is suitable for instruments which have been administered in many countries. Second, a domain-based meta-analysis used a thematic domain from which culture-comparative studies are sampled instead of one specific instrument or method
Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population
No full textData source: Supplemental materials, http://www.bloodjournal.org/highwire/filestream/359816/field_highwire_adjunct_files/0/blood-2016-05-718171-1.pdfDespite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs.Nadine Hein, Donald P. Cameron, Katherine M. Hannan, Nhu-Y N. Nguyen, Chun Yew Fong, Jirawas Sornkom, Meaghan Wall, Megan Pavy, Carleen Cullinane, Jeannine Diesch, Jennifer R. Devlin, Amee J. George, Elaine Sanij, Jaclyn Quin, Gretchen Poortinga, Inge Verbrugge, Adele Baker, Denis Drygin, Simon J. Harrison, James D. Rozario, Jason A. Powell, Stuart M. Pitson, Johannes Zuber, Ricky W. Johnstone, Mark A. Dawson, Mark A. Guthridge, Andrew Wei, Grant A. McArthur, Richard B. Pearson and Ross D. Hanna
Cultural diversity and work-group performance: Detecting the rules
No full textWith greater levels of international cooperation, work-groups are increasingly composed of members from different cultures. These groups often suffer from communication problems; however, research suggests that they also benefit from their members cultural diversity and generate higher ranges of problem perspectives. This thesis investigates two questions: first, when do diverse groups generate a higher range of perspectives; second, which skill do group members need to benefit from cultural diversity? In order to investigate the conditions for diversity benefits, student groups of high national diversity were compared with student groups of low national diversity while working together creating a new game. Empirical findings suggest, first, cultural diversity inhibits idea generation in the initial stage; second, cultural diversity affects communication much less then expected, and, third, the absence of communication difficulties is no sufficient condition for achieving the diversity benefits. The author concludes that without training, group members have difficulty detecting cultural differences that could lead to greater idea variation. Hence, the second part of the thesis proposes a training method for the skill to detect cultural differences. An evaluation study of the training method comparing trained with un-trained students supports the effectiveness of the training method
Social Motives and Their Development in Cultural Context
No full textThis paper deals with differences in social motives between cultures and with respect to their development. First, social motives are described as complex functional systems. Then aggressiveness and achievement motivation are dealt with as examples. Assumptions about biological factors are discussed and cultural differences are reported. Based on cross-cultural research, variations in early mother-child relations and in cultural norms and values are discussed as main sources of individual and cultural differences
Increasing the resilience of urban areas to extreme precipitation: Are the residents ready?: The receptivity for effective rainproof measures on private terrain in the neighbourhood De Baarsjes, Amsterdam
No full textWater challenges the livelihood of all living beings through its scarcity and its abundance. Due to climate change these extremes will intensify in the future. As mankind continues to cluster in economic centre points, housing areas as well as infrastructure increases. This situation forces the water to run off rather than infiltrate. Inundated areas place a threat to health and mankind will be forced to increase the resilience in urban areas. Adaptation to more extreme weather situation on private terrain is necessary as private space contributes 50% of the area. In order to stimulate inhabitants to adapt different measures it is essential to get an idea of their receptivity. The receptivity model of Jeffrey and Seaton (2009) offers a framework to understand with which of the 4 A’s (Awareness, Association, Acquisition and Application) residents are struggling most. A sequential mixed method of combining questionnaires and focus groups was used to collect data on residents’ receptivity and perceived effectiveness of potential rainproof measures. Additionally, the hydrologic expected effectiveness of selected rainproof measures was analysed with help of the Adaptation Support Tool and compared to the perceived effectiveness. Although residents are developing all 4 A’s simultaneously to different extend and speed, it appears that residents are struggling with Awareness. Their experience with flooding and water damage reveals awareness of the issue itself; however, hesitation to implement countermeasures was noticed. The awareness of solutions is missing for more than half of the respondents. The association with their own agenda and recognising the benefits is not yet widespread among residents. The acquisition requirement of receptivity – the knowledge about implementation, operation and maintenance – is missing. It is evident that the application requirement cannot be accomplished as acquisition is absent. Residents demand additional information. The development of the 4 A’s, specifically Association and Acquisition, require more attention. Residents recognise their own responsibility for the private lot, but also shared responsibility and thus community actions are expected. Residents insist that the municipality and Waternet fulfil their tasks within their responsibilities. Transparency and communication with residents are important features, whereby provision of tailor-made advice has high importance. Recognising responsibilities and also dependencies between different stakeholders as well as knowledge requests reveal lacking receptivity and further encouragement is required. Frontrunners can hereby play an important role. The effectiveness of countermeasures is an important consideration for increasing resilience. Evidently respondents indicated rainwater barrels as possible measure to temporarily store water. Green roofs were also well known. The perceived effectiveness scored relatively high for all temporary water storage measures. The Adaptation Support Tool (AST ) calculated effectiveness between 2% and 42%, where this is a percentage of a 60mm precipitation storage target. The highest effectiveness of 42% is achieved by intensive green roofs, whereas the costs are relatively high. A rainwater pond on the other hand has low investment and maintenance costs and scored an effectiveness of 22%. Green gardens reveal higher costs, but also greater effectiveness. It is expected that all gardens already have some green spaces and a simple intervention as reducing tiles could contribute up to 30% of the target. The calculations demonstrate that none of the measures could achieve the target alone. A combination is required, whereby the order of implementation can be guided by their effectiveness and costs. For improving receptivity of residents, several points should be considered. First of all connect residents with similar issues, they possibly motivate each other and develop an urge to action. Tailor-made information improves information distribution. Residents are reluctant due to unfamiliarity with alternatives for their specific situation. It is also important that residents are aware of the effectiveness and the costs of measures for when they need to chose. The AST calculations give insight in the effectiveness and costs of measures. Transparency of tasks, responsibilities and choices of the municipality, Waternet and Amsterdam Rainproof could provide a positive mindset towards the implementation of rainproof measures. Communication about (possible) barriers might be helpful in order to prepare residents. It is important that the municipality promotes climate adaptation throughout the entire legal and organisational levels.Water Managemen
Social capital and self-rated health in the Republic of Ireland: evidence from the European Social survey
No full textThis paper analyses the determinants of self-reported health in Ireland, conditioning self-reported health on a set of socio-economic, labour market and social capital variables. Ireland has the highest self-reported health rate in Europe, a finding backed-up by other studies. Data were derived from the 2002 and 2005 European Social survey. The full 87,915 observations from both rounds were pooled and used to estimate mean self-rated health across Europe. The Irish data were isolated, totalling 2,049 individuals for 2002 and 2,286 individuals for 2005. The 2002 data were used to analyse the determinants of subjective health state, as it had a richer array of social capital variables. The results demonstrate statistically significant effects of income on self-reported health that are robust to different statistical specifications and statistically significant though modest effects of social capital variables such as associational membership and frequency of social meeting and labour market variables such as being on a limited as opposed to permanent contract
Public perceptions and community issues
No full textThis paper is the seventh in a series of 8 that make up the evidence base for SDC report 'The role of nuclear power in a low carbon economy'.Publisher PD
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