<p dir="ltr">Metastatic breast cancer (MBC) and consequent dormancy present a significant clinical challenge due to recurrence and relapse. It is thus pivotal to understand the mechanisms which can reawaken the dormant cancer cells into a proliferative phenotype, and to develop effective therapeutic strategies to eradicate the minimal residual disease. Fibroblast Growth Factor Receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) which is amplified in MBC and plays a key role in cancer cell plasticity. Interestingly, while dormant cancer cells also exhibit high FGFR1 expression levels; still, mere FGFR1 alone is insufficient to drive proliferation without FGF2 ligand induced receptor activation. In accordance with previous data, we report elevated levels of FGF2 in serum of mice with diet induced obesity (DIO), thereby indicating a potential link between obesity and dormancy breakage. We demonstrate that serum from obese animals, exogenous FGF2 stimulation, or constitutive stimulation through autocrine and paracrine FGF2 is sufficient to induce proliferation and drive pulmonary outgrowth of the dormant D2OR model. Additionally, blockade of FGFR signaling via FGFR kinase inhibitors prevented ligand induced outgrowth of the D2OR model. Importantly, FGFR1 overexpression in normal mammary epithelial cells also requires FGF2 signaling to induce transformation suggesting that mere FGFR1 amplification alone is not a driving event.</p><p dir="ltr">Despite elevated FGFR1 expression levels in dormant and metastatic breast cancer, FGFR kinase inhibitors have been unsuccessful in inducing a significant therapeutic response in FGFR1-amplified setting, potentially due to the inability of targeting the kinase-independent functions of FGFR1. In our study, we explored the use of G-quadruplex (G4) stabilizers as epigenetic therapeutics to limit FGFR1 expression, thus targeting both kinase-dependent and independent functions of the receptor. Our findings demonstrate that, in contrast to the FDA approved FGFR-kinase inhibitors, G4 stabilizers significantly reduce the viability of dormant cells in 3D culture models. Additionally, the G4 stabilizers effectively suppressed the expression of other oncogenes such as PDGFR and MYC, which is advantageous given the heterogeneous nature of dormant and MBC cells. The results from our findings suggest that FGF2:FGFR1 signaling acts as a key molecular mechanism in modulating dormancy and breast cancer progression. Additionally, G4 stabilizers hold promise as a novel therapeutic approach to target and eliminate dormant breast cancer cells, potentially reducing the risk of relapse and improving long-term patient outcomes.</p>

Thesis (Ed.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / This study investigated the relationship between an instructional pedagogy formulated around Polya's heuristic four-step method and computer based problem solving performance in an introduction to computer programming course. A four step heuristic managerial guide, employing structured walkthroughs and group activities, was developed to direct students into a period of constructive reflection, planning, and refinement supporting structured programming. The subjects consisted of fifty-four secondary school seniors, completing a first course in BASIC programming, evenly divided into an experimental group and a control group. The experimental group received instruction related to the heuristic managerial guide. The control group received instruction similar to what was normally provided them without the guide. Four problems were introduced and analyzed, within a lecture format, followed by a question-answer session. Each subject attempted to complete a problem-set consisting of a problem and three related extensions. After a week, results were evaluated and scores from zero to four were assigned based on the number of correct solutions attained. No qualitative evaluation was performed. The null hypothesis stated that the two sets of scores came from populations having identical distributions. Since a normal distribution was questionable, the statistic used was the Mann-Whitney U test, a nonparametric version of the t-test for independent samples. The ranked scores for the two groups appeared to support the research hypothesis, since the sum of ranked scores for the experimental group exceeded those of the control group 840 to 645. However, the results of the Mann-Whitney test did not support a rejection of the null hypothesis at the 5% level of significance. The value, z = 1.791, was sufficient to support the rejection of the null hypothesis at the 7% level. Therefore, the heuristic managerial guide showed a tendency to positively contribute to student performance on the problem set used in the study. The conclusion drawn was that the heuristic managerial guide yielded encouraging, but not significant, results when applied to a computer based problem set. Further research into this approach should consider the effects of the method if implemented at the inception of the students' first course. / 2999-01-01

In this thesis, the first chapter provides the general description of this interpreter. The second chapter contains a formal definition of the syntax of BASIC along with an introduction to the semantics. The third chapter contains the design of data structure. The fourth chapter contains the description of algorithms along with stages for testing the interpreter and the design of debug output. The stages and actions-are represented internally to the computer in tabular forms. For statement parsing working syntax equations are established. They serve as standards for the conversion of source statements into object pseudocodes. As the statement is parsed for legal form, pseudocodes for this statement are created. For pseudocode execution, pseudocodes are represented internally to the computer in tabular forms.

O cancro de pulmão é a neoplasia com maior incidência e maior taxa de mortalidade em todo o mundo, sendo o diagnóstico em estadios avançados o principal determinante de mau prognóstico. Novas terapias, como a imunoterapia, melhoram a sobrevivência global, mas apenas 30-40% dos doentes respondem a esses tratamentos, atribuindo-se essa baixa resposta a vias alternativas de imunossupressão, adotadas pelos tumores de pulmão, incluindo macrófagos associados a tumores (TAM). CSF-1 está implicada no recrutamento e diferenciação de TAM, bem como na angiogénese tumoral, em especial via um subgrupo de macrófagos que expressa o recetor Tie-2, que respondem à angiopoietina-2 (Ang-2). Neste trabalho, avaliou-se o papel dos níveis séricos de CSF-1 no prognóstico do cancro do pulmão de pulmão de células não-pequenas (CPCNP) e se estes podem servir de biomarcadores de deteção de CPCNP, juntamente com Ang-2. Realizamos um estudo prospetivo que incluiu 145 doentes com CPCNP e 30 indivíduos saudáveis. Os níveis séricos de CSF-1 e Ang-2 foram medidos por ELISA antes da realização de qualquer tratamento. Existe uma forte correlação entre os níveis séricos de CSF-1 e Ang-2 (p<0.000001). Indivíduos com níveis séricos elevados de CSF-1 mostram um risco dezassete vezes superior para apresentarem CPCNP e fenótipos com elevação simultânea de níveis séricos de CSF-1 e Ang-2 estão associados a pior prognóstico do CPCNP. Dado que a expressão elevada combinada de CSF-1 e Ang-2 parece estar presente em doentes com pior prognóstico, seria interessante conhecer a base desta interação, explorando a relação entre as duas as moléculas. Para além disto, pensamos que o CSF-1 poderá ser incluído como biomarcador em protocolos de rastreio de CPCNP, visando a melhoria do valor preditivo positivo das formas de rastreio atualmente delineadas, aumentando a relação custo-efetividade e melhorando a sobrevivência global dos doentes ao permitir diagnósticos mais precoces. / Lung cancer is the most incident and lethal form of cancer, with late diagnosis as a major determinant of its bad prognosis. Immunotherapies targeting immune checkpoints improve survival, but positive results encompass only 30-40% of the patients, possibly due to alternative pathways to immunosuppression, including tumor associated macrophages (TAM). CSF-1 is implicated in TAM differentiation and recruitment to tumors and in tumor angiogenesis, through a special setting of Tie-2-expressing macrophages, which respond to Angiopoietin-2 (Ang-2). We evaluated the role of serum levels of CSF-1 in NSCLC prognosis and whether these could serve as biomarkers for NSCLC detection, along with Ang-2.We prospectively studied an unselected cohort of 145 NSCLC patients and a group of 30 control individuals. Serum levels of Ang -2 and CSF-1 were measured by ELISA prior to treatment. Serum levels of CSF-1 and Ang-2 are positively correlated (p<0.000001). Individuals with high serum levels of CSF-1 present a seventeen-fold risk for NSCLC development and patients with combined High Ang-2/CSF-1 serum levels present a 5-fold increased risk of developing NSCLC. High Ang-2/CSF-1 phenotype is also associated with worst prognosis in NSCLC. Combined expression of CSF-1 and Ang-2 seems to contribute to worst prognosis in NSCLC and it is worthy to understand the basis of this unexplored partnership. Moreover, we think CSF-1 could be included as a biomarker in NSCLC screening protocols that can improve the positive predictive value of the current screening modalities, increase overall cost effectiveness, and potentially improve lung cancer survival.

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