A systems approach to uncovering the adaptive response of cancer to targeted therapies

Thesis (S.M.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 47-53).Tyrosine kinase inhibitors have significant promise in the fight to develop agents that can target cancer in a tumor-specific manner. A number of drugs have been and are currently in development to inhibit specific kinases that can mediate uncontrolled proliferation; however, an unfortunate eventuality for most patients receiving these treatments is the development of resistance that renders these drugs almost completely ineffective. While a number of mechanisms can evolve within a tumor to mitigate effects of kinase inhibitors, we sought to uncover what changes are occurring in the tyrosine phosphorylation network at both short timescales (minutes to 72 hours) and long timescales (120 hours+) that can be playing a role in helping a tumor become resistant to driver-kinase inhibition. It is our hypothesis that specific feedback networks are able to detect and overcome driver kinase inhibition through activation of potential other pathways, which can go on to mediate a longer term resistance phenotype. In order to probe dynamics in the tyrosine phosphorylation network, we employed mass spectrometry to analyze peptides derived from six non-small cell lung cancer cell lines that we classify as either EGFR+ or EML4-ALK+. From both mass spectrometry data and growth assays, we identified an unintuitive boost in signaling and growth in response to low inhibitor concentrations, suggestive of a cellular mechanism that is adaptive to driver kinase inhibition. Studies of EML4-ALK driven H3122 cells showed that this short-term response is not the same as the known long-term resistance mechanism to ALK inhibition, leading support to the notion that the short-term "adaptive response" may be a novel type of mechanism to aid tumor adaptation to targeted therapies. In an effort to better probe signaling events occurring downstream of the phosphotyrosine network, a new pull down technique for mass spectrometry using 14-3-3 protein against phosphoserine and phosphothreonine peptides is described. The results of these studies open up many potential avenues for further exploration into the immediate and long-term signaling response of cancer to targeted therapies.by Adrian Joseph Randall.S.M

Low Carbon Resilient Development and Gender Equality in the Least Developed Countries

The issue of gender equality and climate change has come to the fore in both policy and research arenas in the last decade, due to the widespread recognition that neither the impact pathways for climate change, nor the policy responses are gender-neutral. Whilst it shouldn't be assumed to always be the case, climate change can worsen existing conflicts and gender inequalities, and some strategies to address climate risks can exacerbate this if not applied with gender-sensitive principles. Gender-sensitivity is therefore a key priority for lowcarbon climate resilient planning at local, national and international levels

Evaluation of Community Jobs Scotland Programme

The final evaluation report for the Community Jobs Scotland (CJS) programme for 2011/1

Estimating nonresponse bias and mode effects in a mixed mode survey

In mixed-mode surveys, it is difficult to separate sample selection differences from mode-effects that can occur when respondents respond in different interview settings. This paper provides a framework for separating mode-effects from selection effects by matching very similar respondents from different survey modes using propensity score matching. The answer patterns of the matched respondents are subsequently compared. We show that matching can explain differences in nonresponse and coverage in two Internet-samples. When we repeat this procedure for a telephone and Internet-sample however, differences persist between the samples after matching. This indicates the occurrence of mode-effects in telephone and Internet surveys. Mode-effects can be problematic; hence we conclude with a discussion of designs that can be used to explicitly study mode-effects

Fostering social change through community engagement: A critical insight into strategic knowledge and identity during domestic professional internships in Spanish for specific purposes

abstract: This linguistic ethnography follows three journalism students (Petra, Penélope, and María) as they engaged in experiential language learning (EX-LL) via collaboration with community members during their Spanish for Specific Purposes (SSP) internship sites in the fields of journalism and medicine within the local Metro Phoenix community. Data were collected over the course of a 15-week semester via ethnographic methods (field notes, interviews, observations, and participant-reported data) to explore how the interns (i) took advantage of their SSP internship experiences to engage in identity work that exceeded the goals of the program and how they (ii) implemented their strategic knowledge via communicative strategies (CSs) during breakdowns in communication with community members related to their SSP internship sites/the social function of such strategies. In order to answer the first research question, the data were analyzed via open and focused coding (Dyson & Genishi, 2005), followed by discourse analysis (Gee, 2005) informed by Critical Applied Linguistics (Pennycook, 2001) and Positioning Theory (Davis & Harré, 1990). To answer the second question, all instances in which the interns implemented communicative strategies were analyzed based upon the categorization repertories established by Dörnyei and Scott (1995a, 1995b, 1997), Lafford (2004), and Tarone and Yule (1987). To go beyond understanding what the interns were saying to why were they saying it, discourse analysis was used (Gee, 2005). The findings show that Petra, Penélope, and María appropriated their SSP internship to engage distinct, yet interrelated language- and ethnic/racial-based identity work. Each intern utilized language (and extra-linguistic elements, such as corporeal expression) to position themselves in different ways within social discourse. Furthermore, this identity work influenced which CSs they utilized, as the social function of many of these strategies was to maintain and/or protect their desired identities. Drawing on these insights, a variety of implications are offered from four viewpoints: implications for (i) EX-LL-based research: colonized versus humanizing research, (ii) critical community collaboration inside and outside of EX-LL, (iii) CSs and communicative competence, and (iv) EX-LL/Languages for Specific Purposes pedagogy and internship design.Dissertation/ThesisDoctoral Dissertation Spanish 201

Financial Inclusion and Innovation in Africa: An Overview

Financial inclusion is gaining attention in African policy circles in view of the recent African growth renaissance, but which has been characterised as non-inclusive. While not conclusively documented in the literature, financial inclusion is viewed among the drivers of inclusive growth. This special issue takes a stock of the extent of, and the factors affecting financial inclusion; the role of cross-border banking in financial deepening and access across Africa and the impacts of financial innovation on access as well as monetary policy. While Africa's banking systems are still shallow relative to peers, substantial progress has been made over the past two decades both in terms of financial inclusion and financial innovation, as well as cross-border banking. While access to finance has improved, the evidence based on the Global Findex database points to substantial heterogeneity within sub-regions of Africa and demographic characteristics. The evidence also suggests that foreign banks from emerging markets, including Africa, have contributed to financial access, but the opposite is the case for foreign banks from Europe and USA. However, challenges remain, including the gap between financial deepening and financial inclusion

Towards an educational diabetes model

We are developing a mathematical model to serve as the heart of an educational diabetes simulator. The model is based on physiological principles and consists of three compartments: the gut, the plasma and the interstitial fluid. Glucose and insulin in- and outflow is described for all three compartments using integral/differential equations. The model can be adjusted to predict glucose and insulin concentrations for healthy persons, patients with diabetes type 1 or patients with diabetes type 2. The differences are accomplished by using different values for the parameters of the model. We have performed parameter estimation on data of healthy persons and on data of patients with diabetes type 1. This gives us the values for the parameters for these two groups. The results are promising: for healthy people the data is almost perfectly fitted by our model and for patients with diabetes type 1 the trends of the data are predicted adequately. Unfortunately there was no data available to perform parameter estimation for patients with diabetes type 2. The next steps will now be to obtain more data for patients with diabetes type 1 or 2. This will help us further improve the model, in particular the part that describes food uptake, and to incorporate exercise and emotions into the model. It will also enable us to determine the parameter values for the diabetes type 2 model, thus providing us with the last information needed to develop the educational diabetes simulator