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Morgan, Joanne. "The role of CD55 in the tumour environment." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275151.
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Joseph, Adrian. "Optimising polymersomes for imaging tumour and its environment." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/7458/.
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Polymersomes are nano-meter sized vesicles made by the self assembly of amphiphilic co-polymers in water. This work presents the development of polymersomes as a tool for high resolution in vivo optical imaging. High resolution Intra Vital Microscopy (IVM) was made possible by the use of the Window Chamber (WC), a surgical procedure which allows observation of living tissues through an optically transparent glass replacing a section of skin. WC can be used to observe tumour growth and tumour vasculature development (angiogenesis). High resolution imaging of angiogenesis in vivo with polymersomes can give an useful insight in mechanism of angiogenesis, tumour response to anti-angiogenic therapy and the rationale behind the design of polymersomes for speci�c tumour targeting in therapy. In this work we optimised a number of techniques and tools to characterise the interactions of two diff�erent polymersome formulation with three cell types relevant to the tumour microenvironment: tumour cells Mouse Fibrosarcoma Cell (MFC), endothelial cells Small Vessel Endothelial Cells (SVECs) and perivascularlike cells 10T1/2. The techniques used included Reverse Phase-High Pressure Liquid Chromatography (RP-HPLC), Fluorescence Activated Cell Sorting (FACS) and optical imaging. Furthermore, a flow bio-incubator was developed to study the effect of physiologically relevant flow rates on cellular polymersome uptake. Finally, formulations were tested in vivo to assess suitability for optical imaging and polymersomes distribution in tumour vasculature and stroma. Specific image analysis tool were developed to assist the analysis. The results demonstrated that polymersomes can be used for optical imaging in vivo using a WC. The in vitro techniques developed allowed us to quantify the interactions between polymersomes and cells, and the information gained can be translated in vivo to help predict the polymersomes distribution in tumour. Taken together, the methods and results presented here provide a set of tools based on image analysis that allow rational design of polymersomes for in vivo application.
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Zumel, Marne María Ángela 1984. "Environmental factors and brain tumour risk in young people." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668182.
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Risk factors and diagnosis in young people have been little explored, despite brain tumours (BT) is one of the most frequent tumour type in children and adolescents. The purpose of this doctoral thesis is to study 1) the clinical characteristics and symptoms of BTs in young people, based on the international MOBI-Kids case-control study; 2) a systematic review (SR) of the literature on risk of BTs in young people in relation to environmental factors; 3) the BT risk in relation to chemicals present in drinking water and to heavy metals.
The analyses of clinical characteristics revealed that the vast majority of tumours were neuroepithelial (mostly gliomas), followed by embryonal tumours and meningiomas. Overall, the most frequent symptoms were headache, followed by focal neurological signs and symptoms, nausea/ vomiting and visual signs and symptoms, being a 4% of the cases asymptomatic. The average time of diagnosis tended to be short (median 1.42 months), though this varied according to tumour type, age and type of symptom.
I found many studies that showed an association between environmental factors (including tobacco smoke, pesticides and diet, among other exposures) and BT risk in the SR. Because of methodological limitations however, the evidence about the role of these factors in the aetiology of this disease is still uncertain.
Our analyses in relation to water chemicals showed ORs below 1 for exposures to THMs, and ORs above 1 for nitrate exposure, for both pre- and postnatal exposure periods, some statistically significant so. Our analyses of heavy metals showed ORs below 1for exposures to chromium. However, literature is scarce about this association.
Overall, this thesis served to fill a gap in knowledge concerning 1) the clinical characteristics of BT in young people, useful to both clinical practice and aetiological research; 2) causes of this disease; 3) the role of heavy metals and ubiquitous chemicals in water. Further research needs on the aetiology and prevention of BTs in young people are provided.Los factores de riesgo y el diagnóstico en los jóvenes han sido poco explorados, a pesar de que los tumores cerebrales (TC) son uno de los tipos de tumores más frecuentes en los niños y jóvenes. El propósito de esta tesis doctoral es el estudio de 1) de las características clínicas y los síntomas de los TC en los jóvenes, basados en el estudio internacional de casos y controles MOBI-Kids; 2) una revisión sistemática de la literatura sobre el riesgo de TC en jóvenes en relación con factores ambientales; 3) el riesgo de TC en relación con los productos químicos presentes en el agua potable y con los metales pesados. Los análisis de las características clínicas revelaron que la gran mayoría de los tumores eran neuroepiteliales (principalmente gliomas), seguidos de tumores embrionarios y meningiomas. En general, los síntomas más frecuentes fueron dolor de cabeza, seguido de signos y síntomas neurológicos focales, náuseas/ vómitos y problemas en la visión, siendo un 4% de los casos asintomáticos. El tiempo promedio de diagnóstico tendió a ser corto (mediana 1,42 meses), aunque esto varió según el tipo de tumor, la edad y el tipo de síntoma. Encontré muchos estudios que encontraron asociación entre los factores ambientales (incluido el humo del tabaco, los pesticidas y la dieta, entre otras exposiciones) y el riesgo de TC en la revisión sistemática. Sin embargo, debido a limitaciones metodológicas, la evidencia sobre el papel de estos factores en la etiología de esta enfermedad aún es incierta. Nuestros análisis en relación con los productos químicos del agua mostraron unos OR por debajo de 1 para exposiciones a THMs, y OR por encima de 1 para exposición a nitrato, tanto en períodos de exposición prenatales como postnatales, algunos estadísticamente significativos. Nuestros análisis de metales pesados mostraron ORs por debajo de 1 para la exposición al cromo. Sin embargo, la literatura es escasa sobre esta asociación. En general, esta tesis sirvió para llenar un vacío en el conocimiento sobre 1) las características clínicas de la TC en los jóvenes, útiles tanto para la práctica clínica como para la investigación etiológica; 2) causas de esta enfermedad; 3) el papel de los metales pesados y los químicos ubicuos en el agua. Se ha identificado la necesidad de realizar más investigaciones sobre la etiología y la prevención de las TC en los jóvenes.
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Milojkovic, Dragana. "The leukaemic micro environment : The effect of tumour supernatant (TSN)." Thesis, King's College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500072.
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Nilsson, Wiktor, and Emil Andersson. "Cytokine-induced immune cell migration towards tumour cells in a microchip environment." Thesis, KTH, Skolan för teknikvetenskap (SCI), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-195835.
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The purpose of this project was to study the migration patterns of human immune cells in response to human renal cancer cells. This is useful in the study of different cancer treatments and the body’s own response to cancer. Cancer cells can release cytokines which can be detected by immune cells with the correct receptors. The specific type of immune cell that was studied, was the type of lymphocyte called Natural killer cell, abbreviated to NK cell. These lymphocytes have the characteristics that they can differentiate between a cancer cell and a healthy cell, and then have the capability to kill the cancer cell by different means. On the surface of cells there exist receptors. These receptors can interact with signal molecules in the environment near the cell. In this study the effect on the migration caused by the interaction between the receptor CXCR2 and the chemokine CXCL2 have been studied. This was done by transfecting some NK-92 cells with the receptor CXCR2 and the rest with the receptor NGFR then subjecting them to a CXCL2 chemokine gradient. This gradient originated from human renal cancer cells known to produce this chemokine. The specific cancer cells used was the human renal cancer cell line 786-0 which NK-92 cells are known to have the ability to kill when coming in contact with them. It is because of this trait it is of interest to study if the average movement is altered significantly by this receptor induced movement compared to the control NK-92 NGFR. To determine if a significant difference in preferred direction of migration could be discerned between the NK cells expressing either the receptor CXCR2 or NGFR, two analytic methods were devised and applied. The first method was a visualization of the cell migration in the direction of the chemokine gradient, this analyze had no quantitative properties but served as way to determine a general migration. The second, and more precise method involved 3D cell identification, cell tracing, and quantifying the migration. This method yielded quantifiable results that could be analyzed further. A biocompatible microchip with a small passage was utilized to study the migration of the NK cells subjected to this chemokine gradient. Two different approaches to this problem were made. The first approach was to seed the cells onto the chip in a fluid and observe the migration of the sedimented cells the two dimensional surface the glass bottom of the chip constituted. After several attempts with the fluid approach the conclusion was made that because the NK-92 cells aren’t adherent, fluid flows were found to be the main cause for the most of the NK-92 cells movement. A few attempts were made to stop the fluid from flowing over the passage by utilizing a plug placed in the center of the passage during the seeding of the cells and removed before the experiment, but this was without success. Since this flow made all unassisted migration by the cells impossible, no useful data could be obtained from this method. This introduces the second approach which was to suspended the cells in collagen. In these experiment no apparent movement by the NK-92 cells was observed that could originate from fluid movement but did instead seem to be unassisted cell migration. It was found that in an open fluidic environment, fluidic phenomena preponderated the cells own migration, and in the collagen environment the cell migration was to small to yield any obvious results. The analytic methods devised to trace cells and measure the cell migration worked well and gave quantifiable results. In the 3D experiments these methods were able to trace the NK cells and study the migration of the cells with different receptors.
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Ham, Sunyoung. "The role of breast cancer derived-exosomes in the tumour micro-environment." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/208432/1/Sunyoung_Ham_Thesis.pdf.
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The findings in this thesis demonstrate that cancer-derived exosomes play a critical role in the tumour microenvironment, which greatly expands our understanding of the mechanisms underlying cancer progression and metastasis. This research provides novel approaches at allowing improved utilisation of cancer-derived exosomes as diagnostic biomarker tools or for therapeutic interventions for cancer treatment.
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van, Wyk Hester C. "An investigation into the relationships between tumour invasiveness, the tumour micro-environment and survival in patients with primary operable colorectal cancer." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8335/.
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Colorectal cancer is the second commonest cause of cancer-related death after lung cancer. Prognostic features of colorectal cancer are important in determining the optimal treatment for an individual patient. The management of colorectal cancer is further complicated by the need to translate prognosis based on morphology alone as the TNM staging system describes only the anatomical extent of colorectal cancer. However, there are other prognostic factors that have impact on disease progression and can be used as adjuncts to the TNM classification. In particular, features of invasiveness of the tumour may be helpful in the identification of an aggressive phenotype of colorectal cancer and were further investigated. The hypothesis of an aggressive phenotype of colorectal cancer was explored; tumour budding reflects a detachment of tumour cells at the invasive front and presumed to be an early step in the metastatic process. As such, tumour budding has received some attention in colorectal cancer as it has been proposed as an additional factor that may stratify patients into risk categories and therefore considered to be a promising prognostic factor in colorectal cancer. Chapter 2 examined lymphatic invasion (LI) and blood vessel invasion (BVI) in context to the feasibility of methods in routine practice with and without immunohistochemistry. Results suggested the use of immunohistochemistry (IHC) for detection of lymphatic invasion as feasible; D2-40 improved the identification of lymphatic invasion and was associated with N stage. Elastica staining improved detection rates of blood vessel invasion was associated with T stage and had independent prognostic value. However, the usefulness of CD31 could not be demonstrated. 2 Thus, immunostaining with D2-40 as predictor of nodal metastasis has potential as a marker of lymph node metastasis in early stage colorectal cancer. The detection of blood vessel invasion appeared to be optimised by utilising Elastica stain, resulting in improved detection rates and improved prediction of survival. Therefore, the routine use of Elastica was recommended. These results also point to the relative roles of lymphatic and blood vessel invasion in tumour progression and dissemination in patients with colorectal cancer. In Chapter 3, Elastica staining in blood vessel invasion was further investigated. In study A, the impact of Elastica staining was examined by comparing two cohorts of patients before and after the routine implementation of the stain. Despite that Elastica staining has been shown to enhance detection rates of venous invasion with improved stratification of risk for patients with colorectal cancer, the Royal College of Pathologists advise its routine use only as a measure of quality control if venous detection rates are below 30%. Results from this study concluded that detection of venous invasion appeared to be optimised by utilising Elastica/ H&E stain that resulted in improved detection rates and improved prediction of survival. The routine use of Elastica/ H&E staining was therefore recommended. In study B, venous invasion in mouse models based on the most common mutated genes of colorectal cancer were examined. Evaluation of the depth of invasion (T stage) was used as an indicator of the extent of tumour growth and venous invasion was used as indicator of metastatic spread. The results showed that Elastica staining can be of use in the assessment of mouse models as it highlighted the elastin in veins and vascular structures were recorded in all models. However, venous invasion was only present in model 2 suggesting the 3 metastatic potential of this model. Therefore, in Model 2 the addition of activated Kras promoted formation of invasive tumours. Kras has a known role in metastatic colorectal cancer. Therefore, Elastica staining can be used to contribute to the current understanding of metastatic spread in colorectal cancer. Chapter 4 examined tumour invasion in nerves as a potential supplement to the TNM staging system. Metastatic spread can occur in nerves however, the identification of perineural invasion can be difficult with routine staining -H&E (haematoxylin and eosin) alone. Therefore, the prognostic role of perineural invasion (PNI) in Stage I colorectal cancer, using immunohistochemical staining (S100) was investigated. No associations were demonstrated between perineural invasion and clinopathological features. However, the combination of venous invasion and perineural invasion (VI&PNI) were associated with poorer overall survival on univariate analysis while age had independent prognostic value. Therefore, immunohistochemistry using S100 improved the identification of perineural invasion however, alone; the prognostic value was limited unless used in combination with venous invasion. These findings suggested that the detection of early metastatic invasion (Venous/lymphatic/perineural invasion- ―VELIPI‖) in Stage I colorectal cancer can potentially be helpful in the prediction. In Chapter 5 tumour budding were further investigated. First, the prognostic value of tumour budding using of the 10HPF (high powered field) method were examined. H&E slides were used and the number of tumour buds was counted using the 10HPF method. An optimal threshold score for the determination of high-grade budding was performed by a ROC analysis using survival as endpoint. 4 The study concluded that the presence of tumour budding was an independent adverse prognostic factor in patients with primary operable colorectal cancer. Therefore, the 10HPF method demonstrated to be a promising method for the assessment of tumour budding in H&E sections and should be considered for implementation in routine clinical practice. Next , the relationship between tumour budding and clinopathological characteristics, tumour micro-environment and survival in patients with primary operable colorectal cancer were examined. Results showed that tumour budding was associated with TNM stage, serosal involvement, venous invasion and a weaker inflammatory cell infiltrate and more stroma. The study concluded that the presence of tumour budding was associated with elements of the tumour micro-environment and was an independent adverse prognostic factor in patients with primary operable colorectal cancer. Specifically, high tumour budding was associated with and stratified effectively the prognostic value of TNM stage, venous invasion and GMS. Taken together tumour budding should be assessed routinely in patients with primary operable colorectal cancer. Further, the prognostic significance of intratumoural budding were investigated, when compared to peritumoural budding in patients with primary operable colorectal cancer. Results showed that intratumoural budding was an independent prognostic factor, as such supporting further studies to investigate intratumoural budding in a larger cohort of preoperative biopsies applicable to routine clinical use. The work presented in this thesis highlights the importance of the additional factors associated with tumour invasiveness and reports associations with the tumour micro environment and local inflammation in patients with colorectal 5 cancer. In addition, this work adds weight to the body of evidence suggesting that the recognition of an aggressive phenotype may improve stratification of treatment for patients with colorectal cancer. The thesis concluded that additional prognostic factors associated with tumour invasiveness can contribute to the current TNM staging systems and have potential to be implemented with automated assessment for future use in routine practice, the implementation of tumour budding should be further explored.
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Bhaskaran, Ambily. "Tumour suppressor genes in fish : molecular biomarkers for carcinogens in the aquatic environment." Thesis, Brunel University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286800.
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Al-Akra, Lina. "The Effect of The Tumor Microenvironment on Multi-Drug Resistance and the Assessment of Agents that Overcome this Effect." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27974.
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Multidrug resistance (MDR) development is a major obstacle in the fight against cancer, primarily because of the over expression of ATP-binding cassette transporters (ABC transporters) such as P-glycoprotein (Pgp). Pgp typically protects cancer cells through the efflux of a diverse range of cytotoxic chemotherapeutics, such as Doxorubicin (DOX). Recently developed novel iron chelators (i.e., Dp44mT, DpC) demonstrate potent anti-tumor activity in these drug resistance cells. However, while the mechanism of Pgp drug efflux and function is known, the intracellular distribution and role of Pgp is yet to be determined. Additionally, the responsiveness to chemotherapeutics has been shown to be heavily influenced by the microenvironment of tumor cells. Thus, exploring these factors would be beneficial to potentially developing alternative agents and treatments to target MDR.
This thesis consists of 6 chapters: A comprehensive literature review (Chapter 1 Introduction); a general methods chapter (Chapter 2 Materials and methods); 2 result chapters (Chapters 3-4) describing and discussing the results obtained; a concluding discussion of the findings and future directions (Chapter 5 Discussion) and a Bibliography (Chapter 6).
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Visweswaran, Malini. "Implications of the WNT Signalling Pathway for Adipose-derived Mesenchymal Stem Cells in a Breast Tumour Environment." Thesis, Curtin University, 2017. http://hdl.handle.net/20.500.11937/59066.
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This study describes the various roles adipose-derived mesenchymal stem cells (ADSCs) play in a breast tumour environment. The ADSC-derived secreted factors inhibit breast tumour cell growth aspects, whereas the tumour-derived secreted factors transform ADSCs into tumour-associated fibroblasts (TAFs). Additionally, it highlights the role of Wnt antagonist sFRP4 and its peptides to further influence the activity of ADSC-derived secreted factors, to downregulate the transformation of ADSCs into TAFs, and in upregulating the adipogenic differentiation of ADSCs.
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Akarca, Ayse. "Immunohistochemical studies for identification of biomarkers in haematological malignancies: An approach for potential novel therapeutic targets." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1127626.
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Lymphoid neoplasms are a subgroup of haematological malignancies that affect circulating lymphocytes. The clinical and biological heterogeneity of lymphoid neoplasms can lead to difficulty in accurate diagnosis in this group of diseases. The advancement in effective and feasible detection platforms has enabled novel biomarkers to improve diagnosis and prognosis, in addition to assist in patient stratification and personalised treatments for these diseases. Although there have been improvements in high-throughput diagnostic techniques, the conventional immunohistochemistry (IHC) remains the most widely used platform for biomarker assessment in the field of tissue pathology. As this conventional technique has certain limitations, multiplex IHC (MIHC) approaches have found ways to overcome these challenges, therefore becoming the main focus of immunotherapy for lymphoid neoplasms. This particular effective and proficient technology can simultaneously target multiple molecule/protein of interest within the tumor microenvironment to determine the status of immune cell activation and the presence of protein expression. MIHC is advantageous in providing information about the underlying immune evasion mechanisms, which play a vital role in the development of prognostic and diagnostic biomarkers. This thesis focuses on the novel use of IHC/MIHC approaches and their current role in biomarker development to be used in diagnosis, prognosis, and the potential treatment strategies within haematological malignancies in specific lymphoid neoplasms.
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Park, James H. "An investigation into the relationship between the tumour and its environment and survival in patients with operable colorectal cancer." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8308/.
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Colorectal cancer is the second most common cause of cancer death in the Western World. Although staging and prognosis is presently based on pathological assessment of primary tumour invasion and the presence of lymph node and distant metastases, it is increasingly recognised that other factors pertaining to both the tumour and host may similarly affect outcome. The local and systemic environment, encompassing host inflammatory responses and the tumour microenvironment, are examples of such. However, how such measures may compliment present TNM-based staging are not clear. Furthermore, tumour and host factors, both modifiable and non-modifiable, which may determine the local and systemic environment, remain to be fully determined. The present thesis examined the clinical and prognostic utility of assessment of the local and systemic environment, and potential tumour and host factors which may determine these responses. The following conclusions were drawn: Examining patients from the United Kingdom and Japan, Chapter 2 and 3 concluded that assessment of the systemic inflammatory response, utilising the modified Glasgow Prognostic Score, provides further prognostic stratification in addition to TNM stage. Although the proportion of patients exhibiting an elevated systemic inflammatory response differed between populations, the prognostic value was comparable. Chapter 4 validated assessment of the tumour stroma percentage as a prognostic factor independent of TNM stage and the local inflammatory cell infiltrate (cancer-specific survival HR 1.84, 95% CI 1.17-2.92, P=0.009). Chapter 7 further confirmed the prognostic value of a combined tumour microenvironment score, based on assessment of the generalised inflammatory cell infiltrate and tumour stroma percentage, in patients with primary operable colorectal cancer. This score, termed the Glasgow Microenvironment Score, was able to stratify patients into a good prognostic group, with five-year survival of 89%, an intermediate group with a two-fold increased risk of death and five-year survival of 75%, and a poor prognostic group, with a four-fold increased risk of death and five-year survival of 51%. Chapters 5 and 6 identified the presence of mismatch repair deficiency and activation of the JAK/STAT3 as two potential mechanisms which may determine host local and systemic inflammatory responses. However, the prognostic value of such candidate mechanisms was weak, suggesting that other pathways and tumour characteristics are implicated, and that molecular heterogeneity is likely to play an important role in determining not only the local and systemic environment, but also outcome. Chapter 9 concluded that the Immunoscore, an immunohistochemistry-based assessment of T-lymphocyte density within the tumour microenvironment, held greater prognostic value than assessment of the generalised inflammatory cell infiltrate using the Klintrup-Mäkinen grade. However, assessment of tumour stroma percentage provided additional prognostic value irrespective of the methodology employed to examine the local inflammatory cell infiltrate. Furthermore, the results of Chapters 7, 8 and 9 together suggested that loss of the local, anti-tumour immune infiltrate was the primary event which allows continued tumour growth, development of a tumour-supportive microenvironment and propagation of a systemic inflammatory response. Chapter 10 concluded that pre-diagnosis use of aspirin but not statins was associated with a lower modified Glasgow Prognostic Score, despite strong associations with comorbidity and BMI. This did not translate into an improvement in survival, potentially reflecting the underlying indication for use of these drugs primarily as cardiovascular secondary prevention medications. Finally, Chapter 11 examined the clinical utility of assessment of the tumour microenvironment using colonoscopic biopsy specimens, concluding that the use of biopsy-derived specimens was feasible. Furthermore, in addition to identifying patients who may benefit from therapies targeting the tumour microenvironment, assessment of a biopsy-derived Glasgow Microenvironment Score had comparable prognostic value to full section assessment of the tumour microenvironment.
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Zhuang, Lihui. "Mechanisms of microenvironmental conditioning in non-Hodgkin's lymphoma." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6486.
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Tumours are not autonomous transformed cell populations, but rather a society composed of both malignant and normal, including immune, cells that together foster tumour growth and development. Tumour-associated macrophages have been reported to enhance tumour growth, progression and metastasis. In high-grade non-Hodgkin’s lymphomas, prototypically the B-cell neoplasm, Burkitt’s lymphoma (BL), infiltrating macrophages engulf large numbers of apoptotic tumour cells. Evidence suggests that apoptotic BL cells can condition the tumour microenvironment to promote lymphoma development by selectively attracting macrophages while inhibiting neutrophil infiltration and by stimulating macrophages to produce the B-cell growth and survival factor. Tumour cells grow in a hypoxic and nutrient-deficient environment and the resultant cellular stress can induce apoptosis. It is therefore possible that hostile environmental conditions in the tumour also contribute to the generation of a pro-tumour microenvironment. This thesis describes investigations which examined this hypothesis. BL cells were cultured at high density to mimic conditions of metabolic stress existing in the tumour environment. Cell-free supernatants from such stressed BL cells demonstrated potent chemoattractive activity for mononuclear phagocytes. Supernatants from BL cells that were protected from apoptosis by over-expression of bcl-2 had similar ability, confirming that chemoattractant release was apoptosis-independent. The observation that apyrase and suramin could inhibit the chemotactic activity of these supernatants suggested that nucleotides might be the apoptosis-independent chemoattractant. Detection of ATP in stress supernatants by bioluminescence assay was consistent with this proposal. Significantly, supernatants from BL cells and those transfected with bcl-2 were both found to inhibit neutrophil migration, suggesting the occurrence of a neutrophil migration inhibitory factor whose release was apoptosis-independent. Furthermore, stress supernatants could promote BL cell proliferation in vitro, which was apoptosis and cell line-independent. In order to study the role of TAM in the tumour microenvironment, a novel macrophage model was devised using mouse embryonic stem cells (ES cells). Cells derived from ES cells generated in vitro expressed macrophage-specific markers and were free of dendritic cells and undifferentiated ES cells. ES cell-derived macrophages (ESDM) could migrate towards apoptotic BL cells and engulf them. However, ESDM migrated to stress supernatants with decreasing efficiency as they matured. Preliminary data indicated that the phagocytic ability of ESDM to engulf apoptotic cells increased as they matured, consistent with distinct roles for circulating monocytes and tissue macrophages with regard to this function. Considering the high yields and purities of ESDM described here, together with their non-malignant nature and genetic versatility these cells should provide a superior source of undifferentiated mononuclear phagocytes with which to elucidate the molecular mechanisms underlying tumour infiltration and microenvironmental conditioning by TAM. In conclusion, this work suggests that under conditions of pre-apoptotic stress, BL cells have the capacity to regulate their micro-environment upstream of their apoptosis programme to promote net tumour growth through paracrine signals that attract supportive macrophages and inhibit destructive neutrophils and through release of autocrine/juxtacrine tumour growth factors.
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Chaddad, Hassan. "Development of vascularized tumor spheroids mimicking the tumor environment : angiogenesis and hypoxia." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ001.
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Le microenvironnement tumoral, l'angiogenèse tumorale et l'hypoxie jouent un rôle crucial dans la progression tumorale et le développement de thérapies de nombreux cancers. Les limites de pénétration des médicaments, les phénomènes de résistance aux anti-cancéreux, la vascularisation de la tumeur et l’hypoxie sont tous des paramètres influençant les effets du médicament. La culture cellulaire 3D permet de créer un microenvironnement qui imite l’architecture et la fonction des tissus in vivo. L’expression de gènes et de protéines modifiée par l’environnement 3D est une autre caractéristique qui impacte l’effet d’une molécule thérapeutique. Dans notre première étude, afin de développer un modèle 3D vascularisé imitant celle des tumeurs in vivo, nous avons mis en culture des cellules endothéliales en 2D avec des cellules tumorales en 3D. Après 2 semaines de culture, un réseau vasculaire s’est organisé avec des structures de type tubulaire présentant une lumière et exprimant différents marqueurs angiogéniques tels que VEGF, CD31 et Collagène IV. Dans notre deuxième étude, nous avons développé un modèle d’hypoxie in vitro intégrant l'environnement 3D et un agent mimétique de l'hypoxie (CoCl2). Le but de ce modèle est de créer un modèle d'hypoxie imitant les tumeurs in vivo et de montrer l'importance de l'hypoxie dans la réponse et la résistance aux médicaments. Ces résultats ont révélé que la meilleure condition était la combinaison 3D+CoCl2, conduisant à la surexpression des gènes relatifs à l’hypoxie (GLUT1/3, VEGF) et à la résistance aux médicaments (ABCG2, MRP1). L'angiogenèse et l'hypoxie sont des facteurs clés pour le microenvironnement tumoral in vivo et ils doivent être adoptés dans la conception de modèles tumoraux in vitro pour mieux sélectionner et cribler les médicaments anticancéreuxThe tumor microenvironment, tumor angiogenesis, and hypoxia play a critical role in the tumor progression and therapy development of many cancers. Limitations in drug penetration, multidrug resistance phenomena, tumor vascularization, and oxygen deficiency are all parameters influencing drug effects. 3D cell culture allows to create a microenvironment that more closely mimics in vivo tissue architecture and function, thus, gene and protein expression modified by the 3D environment are further features that affect treatment outcome. In our first study, in order to develop a vascularized 3D model like in vivo tumors, we co-cultured 2D endothelial cells with 3D tumor cells. After 2 weeks of this combination, a vascular network was formed and organized with tubule-like structures presenting a lumen and expressing different angiogenic markers such as VEGF, CD31 and Collagen IV. In our second study, we developed an in vitro hypoxia model integrating the 3D environment and a hypoxia mimetic agent (CoCl2) to mimic the in vivo tumors and to show the importance of hypoxia in drug response and resistance. Results revealed that the best condition was the combination 3D+CoCl2 model, leading to overexpression oh hypoxia (GLUT1/3, VEGF) and drug resistance (ABCG2, MRP1) related genes. Taken together, angiogenesis and hypoxia are key factors for in vivo tumor microenvironment and they should be adopted in in vitro model design to better select and screen anticancer drugs
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Smith, Hannah. "Metabolic adaptations to micro-environmental stress in tumour spheroids." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:3651d265-ddc0-4258-b3f7-2a0242697d21.
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Alterations in energy metabolism due to factors including cellular stress from the hostile tumour micro-environment are a emerging cancer hallmark. Distinct hypoxic and quiescent cell populations develop, which are resistant to chemotherapy due to lack of proliferation, drug inactivity in the altered redox status of the cell and enhanced drug biotransformation. The present study characterises the metabolic strategies employed by these distinct populations of cancer cells. The in vitro 3-dimensional tumour spheroid model, which reflects tumour architecture and behaviour, cultured under different micro-environmental conditions was utilized in this study. Metabolic enzyme activity and expression, overall metabolic flux rates for nutrients, metabolomics profiles of specific pathways and tissue status were assessed. Metabolic adaptations consistent with the Warburg effect were observed in fully oxygenated, proliferative tumour spheroids, with glucose being metabolised to produce lactate. Additionally, metabolomics investigations determined glucose was metabolised by the pentose phosphate pathway, demonstrated by high enrichment of glucose-derived carbon in 6-phophogluconate. The extraction of 39.7 ± 7.6 μ moles (mg protein) -1 glutamine from the medium over 24 hours was observed in these spheroids, consistent with glutaminolysis pathway activity. A 2-fold higher rate of glycolytic flux (measured by production of 3h2O from 5-3H-glucose) was measured in hypoxic tumour spheroids, despite reduced levels of glycolytic enzymes being determined. Surprisingly, although lower rates of glycolysis (2.6-fold) were measured in quiescent spheroids, increased glycolytic enzyme activities (HK 1.9 fold, PK 2 fold and LDH 1.8 fold), glucose (1.9 fold over 24 hours) and glutamine uptake (5.5 fold over 12 hours) as well as lactate production (1.8 fold) were measured, relative to their proliferating counterparts. This study demonstrates that metabolic strategies employed by tumour spheroids differ upon exposure to distinct micro-environmental stresses, additionally identifying hexokinase as a potential therapeutic target for the inhibition of glycolysis under all micro-environmental stress conditions analysed.
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Nachum, Ofir. "Simulating self-assembly of nanoparticles in tumor environments." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/91849.
Full textAbstract:
Thesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2014.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 59-61).
Self-assembly is important in nanomedicine and increasingly plays a role in drug-delivery or imaging applications in tumors. Predicting behavior and dynamics of nanoparticle systems is very difficult, especially when assembling and disassembling particles are involved. To address this challenge, the Bhatia lab has developed NanoDoc (http: //nanodoc.org), an online game that allows users around the world to design and simulate nanoparticle treatments. During this project, we were able to implement mechanisms to effectively describe and simulate self-assembly in NanoDoc. As a bench mark for our simulator, we show that we are able to reproduce laboratory experiments in the literature. The simulator was then made available to the crowd and a challenge was proposed that requires users to perform self-assembly in a scenario aimed at improving the accumulation of imaging agents in tumors.
by Ofir Nachum.
M. Eng.
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Riffle, Stephen. "Multicellular Tumor Spheroids as a Model to Study Tumor Cell Adaptations within a Hypoxic Environment." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin151188562556805.
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Avecilla, Vincent E. "ID3, Estrogenic Chemicals, and the Pathogenesis of Tumor-Like Proliferative Vascular Lesions." FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3519.
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Tumor-like proliferative vascular lesions manifest in several diseases such as peripheral arterial disease (PAD) and atherosclerosis (AS) after arterial injury. The cause of the vascular cell dysfunction in PAD patients is not known. Our recent novel discovery shows that inhibitor of differentiation 3 (ID3) is highly expressed in intimal lesions of clinical vascular disease samples. The central hypothesis of our study is: estrogenic chemical induced dysregulation of ID3 target genes is involved in the development of vascular disease. NHANES data analysis demonstrated higher geometric levels of all 6 PCB congeners in both PAD diagnosed participants and participants at risk of AS when compared to the rest of the population. Adjusted models showed association between higher exposure of PCBs, phthalates, BPA, and increased risk of PAD. Furthermore PCB153 was shown to have the highest geometric mean amongst all PCB congeners in both participants diagnosed with PAD and at risk of AS. Gene expression of ID3 & ID3 candidate targets in blood & tissue studies identified ID3 & ID3 candidate target genes as a driver of vascular disease. Overlapping ID3 & ID3 candidate target genes included: ABCB6, ACP1, BYSL, CAD, CDH15, DCBLD2, DHRS3, DNMT1, ID3, MCM4, and NDUFA7. The ID3 target genes involved in the: focal adhesion pathway were ACTN1, COL1A2, COL3A1, COL6A1, CTNNB1, IBSP, ID3, ITGA8, and MYL2; ECM-receptor interaction were COL1A2, COL3A1, COL6A1, IBSP, ID3, and ITGA8; oxidative phosphorylation pathway ATP5D, ATP5H, ATP6V0B, ATP6V0D1, ATP6V1B2, COX5A, COX7C, COX8A, CYC1, ID3, NDUFA1, NDUFA7, NDUFS4, NDUFV1, NDUFV2; and cell cycle pathway ANAPC10, ATM, CDKN2B, E2F5, MCM3, and MCM4. In summary our results showed an association between exposure to PCBs, phthalates, BPA, and increased risk of PAD and AS, and possible molecular mechanisms of interaction of ID3 target genes and estrogenic chemicals involved in PAD and AS.
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Paraskeva, Paraskevas Antonios. "Does a hypoxic operative environment enhance the metastatic potential of tumours?" Thesis, Imperial College London, 2003. http://hdl.handle.net/10044/1/7610.
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Olurinde, Mobolaji O. "Factors contributing to T cell persistence in a tolerizing tumor environment." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/58180.
Full textAbstract:
Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references.
Cancer is a leading cause of death worldwide, accounting for at least 10% of all deaths globally. Current therapies for cancer include surgical excision, chemotherapy and immunotherapy. CD8[+] T cells are adaptive immune cells responsible for eradicating tumor cells. However, these T cells can be rendered ineffective through tolerance. Yet in various mouse models and human patients, tolerant T cells persist. The aim of this project is to identify factors that support T cell persistence in a tolerizing tumor environment. Using a spontaneous prostate cancer model, we study antigen-specific T cells that have been shown to be locally tolerant in the prostate tumor environment. In this thesis, I compare the immune response in normal, antigen bearing, tumor transgenic and tumor-antigen transgenic mouse models. Results show that T cell infiltration and persistence in the tolerizing prostate environment is dependent on the presence of antigen and tumorigenic/tumor-related factors. Although antigen-specific T cells are locally tolerant in the prostate of tumor-antigen transgenic mice, they generally persist in the prostates of tumor transgenic mice regardless of whether antigen is present or not. Further analyses revealed that T cells infiltrate the prostate and can proliferate extensively in the tolerizing tumor environment due to the presence of antigen. Interestingly, antigen-specific T cells are depleted from the spleens of mice that express antigen in their prostates.
(cont.) This depletion from the spleen is correlated with low levels of IL-7R[alpha] expression and the presence of antigen in the prostate. Tumorigenic or tumor-related factors in the prostate also appear to be supporting CD8[+] T cell persistence. This thesis shows that persistence of antigen-specific T cells in the tumor environment is not dependent on IL-15 and IL-7; cytokines known to support proliferation and maintenance of persisting functional CD8[+] T cells. Some potential candidates are also discussed. More investigative work needs to be done to identify the role of these factors on T cell infiltration and persistence. In combination with tolerance-breaking strategies, persisting T cells may be excellent vehicles for delivering site-specific cancer immunotherapy.
by Mobolaji 0. Olurinde.
Ph.D.
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Calhoun, Mark A. II. "Measurement and Variation of the Mechanical Environment in Glioblastoma." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1503252735120506.
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Omabe, Maxwell. "Characterisation of micro-environmental and molecular changes in prostate tumour treated with bicalutamide." Thesis, University of Ulster, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553874.
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Androgen ablation therapy using bicalutamide (BCA) is a first line treatment for advanced localised prostate cancer; patients treated with this drug have an improved quality of life over 1- 2 years, however they frequently develop treatment resistant, metastatic tumours. Evidence from our laboratory has shown that treatment of LNCaP prostate tumour xenografts with BCA causes a significant reduction in intra-tumour oxygenation and vascular collapse over the first 14 days, followed by reoxygenation and reappearance of blood vessels. The current study investigated LNCaP xenografts treated with BCA or vehicle for 28 days. Tumours excised from the dorsum of SCID mice treated with 2mg/kg of BCA or vehicle (day 0 - 28) were fixed and paraffin- embedded. CD34, Ki-67, eNOS, bcl-2, yH2AX, Rad51, Ku70, E-cadherin, Runx-2, and LC3 were evaluated by immunohistochemistry. In addition, the effect of hypoxia on Runx2 and bcl-2 expression was evaluated in LNCaP cells. BCA treatment resulted in significant reduction in MVD and Ki-67 over the first 14 days (P < 0.01), which was followed by a second phase marked by significant increase in both. The autophagic marker LC3 was highest at the time of lowest oxygenation. In addition, the expression of the protein involved in homologous recombination, Rad51, decreased significantly while the non-homologous end joining protein, Ku 70 remained the same in all tumours. Expression of yH2AX showed that DSBs were repaired from day 21 to 28 of BCA treatment. Furthermore, E-cadherin decreased over 28 days; Runx-2 and bcl-2 were significantly increased from day 21 - 28 while eNOS expression was reduced. QPCR showed that hypoxia selected for cells which over-expressed Runx2 and bcl-2. This study has shown that hypoxia-inducing treatment with BCA caused a number of changes including an immediate decrease in MVD and this selected for cells with a more malignant phenotype.
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Evans, Charlotte L. "The biological and therapeutic significance of tumour necrosis. Identification and characterisation of viable cells from the necrotic core of multicellular tumour spheroids provides evidence of a new micro-environmental niche that has biological and therapeutic significance." Thesis, University of Bradford, 2014. http://hdl.handle.net/10454/13961.
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Tumour necrosis has long been associated with poor prognosis and reduced survival in cancer. Hypotheses to explain this include the idea that as aggressive tumours tend to grow rapidly, they outgrow their blood supply leading to areas of hypoxia and subsequently necrosis. However whilst this and similar hypotheses have been put forward to explain the association, the biological significance of the cells which make up necrotic tissue has been largely ignored. This stems from the belief that because a tumour is more aggressive and fast growing it develops areas of necrosis, rather than, the tumour is more aggressive because it contains areas of necrosis. Which came first like the egg and chicken is yet to be determined, however to date most research has only considered the possibility of the former. Viable cells were found in the necrotic core of Multicellular Tumour Spheroids. When examined these cells were found to be different to the original cell line in terms of proliferation, migration, and chemosensitivity. A proteomic analysis showed that these phenotypical changes were accompanied by changes in a large number of proteins within the cells, some of which could be potential therapeutic targets. Furthermore this has led to a new hypothesis for tumour necrosis and its association with poor prognosis. Necrotic tissue provides a microenvironemental niche for cells with increased survival capabilities. Protected from many chemotherapeutics by their non-proliferative status once conditions improve these cells can return to proliferation and repopulate the tumour with an increasingly aggressive population of cells.Yorkshire Cancer Research
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Nedderman, Drew Michael. "TISSUE SPECIFIC EFFECTS OF ADIPOSE STEM CELLS (ASC) IN A MELANOMA TUMOR ENVIRONMENT." Wright State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=wright1288714187.
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Evans, Charlotte Louise. "The biological and therapeutic significance of tumour necrosis : identification and characterisation of viable cells from the necrotic core of multicellular tumour spheroids provides evidence of a new micro-environmental niche that has biological and therapeutic significance." Thesis, University of Bradford, 2014. http://hdl.handle.net/10454/13961.
Full textAbstract:
Tumour necrosis has long been associated with poor prognosis and reduced survival in cancer. Hypotheses to explain this include the idea that as aggressive tumours tend to grow rapidly, they outgrow their blood supply leading to areas of hypoxia and subsequently necrosis. However whilst this and similar hypotheses have been put forward to explain the association, the biological significance of the cells which make up necrotic tissue has been largely ignored. This stems from the belief that because a tumour is more aggressive and fast growing it develops areas of necrosis, rather than, the tumour is more aggressive because it contains areas of necrosis. Which came first like the egg and chicken is yet to be determined, however to date most research has only considered the possibility of the former. Viable cells were found in the necrotic core of Multicellular Tumour Spheroids. When examined these cells were found to be different to the original cell line in terms of proliferation, migration, and chemosensitivity. A proteomic analysis showed that these phenotypical changes were accompanied by changes in a large number of proteins within the cells, some of which could be potential therapeutic targets. Furthermore this has led to a new hypothesis for tumour necrosis and its association with poor prognosis. Necrotic tissue provides a microenvironemental niche for cells with increased survival capabilities. Protected from many chemotherapeutics by their non-proliferative status once conditions improve these cells can return to proliferation and repopulate the tumour with an increasingly aggressive population of cells.
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Higham, Eileen M. "Overcoming dendritic cell-mediated suppression of T cell responses in a prostate tumor environment." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/61236.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references.
Prostate cancer is the most prevalent malignancy in American men, leading to significant mortality each year. This is in part due to a lack of effective treatments for advanced disease. The prostate is considered an ideal organ for cancer immunotherapy, because it is both nonessential and expresses several prostate-specific antigens than could be targeted for an immuno- therapeutic response. However, such therapy is limited by the tolerization of CD8⁺ T cells in tumors, rapidly abrogating anti-tumor responses. In order to better understand the factors necessary to induce, maintain and promote productive T cell responses against cancer, this research has focused on understanding and interrupting critical interactions between CD8⁺ T cells and immunosuppressive networks within tumors. As our model system, we explored CD8⁺ T cell recognition of spontaneous prostate cancer in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. We demonstrated that both naive and effector tumor-reactive T cells are rapidly tolerized in the prostates and prostate draining lymph nodes (PDLN) of TRAMP mice, and that dendritic cells are important factors driving their tolerization. We then developed two novel immuno- therapeutic approaches to locally overcome the suppressive influence of dendritic cells. In one approach, we engineered tumor-reactive T cells to express the immunostimulatory protein CD40 ligand to mature dendritic cells in the PDLN. This work demonstrated for the first time that tumor-reactive T cells could be engineered to deliver stimulatory signals to dendritic cells in tumor environments to enhance the function of adoptively transferred T cells. In a second approach, we injected ex vivo matured, antigen-loaded dendritic cells into tumors to overcome the influence of endogenous suppressive dendritic cells. This work demonstrated for the first time that intratumoral injections of dendritic cells into spontaneous primary tumors could significantly delay the tolerization of tumor-infiltrating effector T cells and reverse the tolerization of resident tumor-infiltrating lymphocytes (TILs), generating new potential therapeutic applications for TILs. These two approaches establish that mechanism-based immuno- therapeutic interventions can be rationally designed to locally interrupt immunosuppressive networks within tumors. As the TILs enhanced through this work are representative of those found in cancer patients, such approaches could have significant clinical impact.
by Eileen M. Higham.
Ph.D.
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Mattiola, I. "CROSS-TALK BETWEEN HUMAN NK CELLS AND MACROPHAGES: INFLUENCE OF THE TUMOR MICRO-ENVIRONMENT." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229562.
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Natural killer (NK) cells are important effectors of innate immune responses providing cellular immunity against tumor-transformed and virally-infected cells. The existence of cross-talks between NK cells and myeloid cells, in particular dendritic cells, is well established, but information on the cross-talk between NK cells and macrophages is scanty. These interactions have been analyzed using an in vitro reconstituted tumoral micro-environment, as a simplified model to define soluble factors involved and/or cell contact dependency.
Autologous human NK cells and monocyte-derived macrophages were obtained from buffy coats of healthy donors after magnetic beads cell purification. Macrophages were polarized into M0, M1 and M2, using well described stimuli. First, the influence of human polarized macrophages on NK cell anti-tumoral activities was studied. The co-cultures between NK cells and macrophages were performed in direct contact or by treating NK cells with macrophage-conditioned media. Activating receptors expression and degranulation ability (CD107a assay) of NK cells were evaluated by flow cytometry. IFN-γ production by NK cells was quantified by RT-PCR and ELISA. Then, the effect of NK cell-derived IFN-γ on macrophage polarization was assessed. Gene expression of markers, cytokines and chemokines well described to characterized M1 or M2 polarization were evaluated by RT-PCR. In parallel, cytokine and chemokine secretion were detected by ELISA.
M1 polarization was required to enhance IFN-γ production and degranulation by resting NK cells. M1 ability to activate NK cells was further confirmed by the upregulation of CD69 activation marker. Importantly, either soluble mediators and direct contact interactions were involved in this process. However, the level of expression of NKp44 and NKG2D resulted increased only when NK cells were treated with M1-conditioned medium (M1-primed NK cells). Higher NKp44 and NKG2D expression correlated with enhanced NK cell degranulation towards altered cells. Although both NK cell subsets upregulated both receptors, M1-secreted IL-1β was responsible for NKp44 induction on CD56dim population, whereas IFN-β released by M1 favored increased expression of NKG2D by the CD56bright counterpart. Importantly, M1 secretion of IFN-β triggered NK cell expression of IL-15 and IL-15Rα, inducing a mechanism of IL-15 cis-presentation. IL-15 cis-presentation strongly enhanced IFN-γ secretion, that was further sustained by 2B4-CD48 interactions during direct co-cultures. On the contrary, NKG2D upregulation was responsible for increased degranulation by M1-primed NK cells. In parallel, IL-15 trans-presentation mediated by M1, together with NKG2D and NKp30 engagement, were needed to trigger NK cell degranulation during direct contact interactions.
On the other hand, IFN-γ secreted by M1-primed NK cells was sufficient not only to downmodulate CD206 and ALOX15 expression by alternatively-activated macrophages, but also to induce pro-inflammatory cytokine (IL-1β and IL-15) and chemokine (CCL-5, CXCL-9 and CXCL-10) production. Importantly, also CD80 and IL-15Rα, which expression is strictly associated to M1 phenotype, were upregulated.
In conclusion, we demonstrate for the first time in a human model that IL-15/IL-15Rα complex plays a key role in the crosstalk between NK cells and M1 polarized macrophages. Both, cis and trans-presented IL-15 favors NK cell secretion of high amount of IFN-γ and enhances NK cell cytotoxic activity towards tumor cells. Furthermore, having determined a functional correlation between M1-derived IL-1β and NKp44 expression, we propose new effects of IL-1β on NK cell biology. Finally, we demonstrate that IFN-γ provided by activated NK cells is sufficient to partially revert the anti-inflammatory phenotype typical of alternatively-activated macrophages into a pro-inflammatory one. This confers to NK cells a potential involvement in TAMs re-education.
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Beig, Niha Ghouse. "PERI-TUMORAL RADIOGENOMIC APPROACHES TO CAPTURE TUMOR ENVIRONMENT FOR DISEASE DIAGNOSIS AND PREDICTING PATIENT SURVIVAL." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1596539894404172.
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Braman, Nathaniel. "Novel Radiomics and Deep Learning Approaches Targeting the Tumor Environment to Predict Response to Chemotherapy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1586546527544791.
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Serpi, R. (Raisa). "Mechanism of benzo(a)pyrene-induced accumulation of p53 tumour suppressor protein in mouse." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514270398.
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Abstract
The tumour suppressor gene TP53 is the most commonly mutated gene in human cancers. The protein it codes, p53, becomes activated as a response to stress signals. When activated, p53 binds to DNA and affects the transcription of its target genes. They then cause cell cycle arrest, DNA repair and/or induction of programmed cell death, thus preventing mutations and cancer. Specific mutations in TP53 are associated with exposure to certain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs). These environmental chemical carcinogens are formed through incomplete combustion of organic material. Benzo(a)pyrene (BP) is commonly used as a model compound for PAH carcinogenesis. BP causes accumulation of p53, but the mechanism of accumulation is not known. The aim of this study was to gain more insight into the p53 protein in the first phases of PAH carcinogenesis in vivo in mouse, using BP as the model compound.
Mice from the inbred C57BL/6 strain were treated topically or intraperitoneally with BP or were exposed to cigarette smoke inhalation. The amount of p53 protein was studied by immunoblotting, immunohistochemistry and immuno electron microscopy, and the mdm2, p21 and p19ARF proteins were studied by immunoblotting. The binding of BP to DNA was measured by synchronous fluorescence spectrophotometry.
The p53 protein was induced in vivo in skin and lung after BP treatment and in lung after cigarette smoke treatment. An increase in p53 was associated with an increase in the amount of BP-DNA adducts. In skin, the induction of p53 was accompanied by induction of the p21 and mdm2 proteins, which are transcriptional targets of p53. This indicates that the in vivo induced p53 is a wild-type protein and functional. In lungs, the induction of p53 was accompanied by a decrease of mdm2 and an increase of p19ARF. These results confirm that BP is metabolized and binds to DNA in mouse tissues and indicate that BP-DNA adducts are the trigger for p53 protein induction. The in vivo regulation of the p53 protein is different in different tissues of C57BL/6 mouse.
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Alexander, Frank. "RTEMIS: Real-Time Tumoroid and Environment Monitoring Using Impedance Spectroscopy and pH Sensing." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5168.
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This research utilizes Electrical Impedance Spectroscopy, a technique classically used for electrochemical analysis and material characterization, as the basis for a non-destructive, label-free assay platform for three dimensional (3D) cellular spheroids. In this work, a linear array of microelectrodes is optimized to rapidly respond to changes located within a 3D multicellular model. In addition, this technique is coupled with an on chip micro-pH sensor for monitoring the environment around the cells. Finally, the responses of both impedance and pH are correlated with physical changes within the cellular model. The impedance analysis system realized through this work provides a foundation for the development of high-throughput drug screening systems that utilize multiple parallel sensing modalities including pH and impedance sensing in order to quickly assess the efficacy of specific drug candidates.
The slow development of new drugs is mainly attributed to poor predictability of current chemosensitivity and resistivity assays, as well as genetic differences between the animal models used for tests and humans. In addition, monolayer cultures used in early experimentation are fundamentally different from the complex structure of organs in vivo. This requires the study of smaller 3D models (spheroids) that more efficiently replicate the conditions within the body.
The main objective of this research was to develop a microfluidic system on a chip that is capable of deducing viability and morphology of 3D tumor spheroids by monitoring both the impedance of the cellular model and the pH of their local environment. This would provide a fast and reliable method for screening pharmaceutical compounds in a high-throughput system.
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Carter, Rachel. "Exploiting the chick embryonic environment to reprogram neuroblastoma cells to a benign phenotype." Thesis, University of Liverpool, 2013. http://livrepository.liverpool.ac.uk/11733/.
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Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia and adrenal medulla. Tumours with MYCN amplification have the worst prognosis, and make up around 30% of neuroblastoma diagnoses. Neuroblastoma exhibits an unusually high propensity for spontaneous regression, which occurs most frequently in the youngest patients (under 18 months of age), perhaps because developmental cues still present prompt belated differentiation of the tumour cells. This led to the hypothesis that factors from an appropriate embryonic environment may be capable of activating the correct molecular switches to encourage the differentiation and/or apoptosis of neuroblastoma cells, reprogramming the tumour to a benign phenotype. To test this hypothesis, EGFP-labelled MYCN-amplified Kelly cells were injected into the extra-embryonic vitelline veins of embryonic day 3 (E3) and E6 chick embryos, and the responses of injected cells were analysed at E10 and E14. Kelly cells injected at E3 respond to neural crest migratory cues and integrate into neural crest-derived tissues: some neural, notably the sympathetic ganglia and enteric nervous system, although never the adrenal gland; and others non-neural, such as the meninges and tail. Cells injected at E6 do not show such targeting, integrating into various tissues such as the liver, kidney and meninges. The cells respond to their respective microenvironments, and in sympathetic ganglia some cells differentiate, show reduced cell division, and crucially such cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. Kelly cells’ morphology, behaviour and gene expression are altered by the sympathetic ganglia microenvironment. Taking these key observations, we speculate that the Kelly cells’ MYCN amplicon may likely contain the required DNA regulatory sequences to enable MYCN expression to be altered in response to the embryonic environment. If the factors responsible for MYCN repression can be elucidated, they may represent effective new therapeutic targets.
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Eben, Jeffrey E. "Combination of Deep Learning and Radiomic Classifiers Within the Tumor and Tumor Environment for Prediction of Response to Neoadjuvant Chemotherapy (NAC) In Breast DCE-MRI." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1575235591194931.
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Bhatia, Maneet. "Inhibition of the Thioredoxin System: Regulation by the Cancer Cell Environment." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367262.
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The oxygen environment in tumors is not static and involves constant cycling between hypoxic and re-oxygenation phases, a phenomenon known as intermittent hypoxia. Hypoxic and redox pathways are upregulated in response to intermittent hypoxia. The thioredoxin system, comprised of thioredoxin and thioredoxin reductase, is one of the main antioxidant systems, while hypoxia inducible factor 1 (HIF1) is the major hypoxia responsive system. High levels of both the thioredoxin system proteins and HIF1α have been correlated with extremely aggressive and highly metastatic tumors. Both these systems have also been linked to development of resistance against anti-cancer therapies. Moreover, HIF1α is indirectly redox regulated by thioredoxin, suggesting a potential cross-talk between the two systems, which becomes more apparent under intermittent hypoxia. Therefore, an understanding of these two systems under different oxygen conditions occurring in cancers may aid in the designing more effective therapeutics.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Xing, Fei [Verfasser], and Peter [Akademischer Betreuer] Bastian. "Towards Agent-based Multi-scale Tumor Growth Modeling: Software Environment and Computational Complexity / Fei Xing ; Betreuer: Peter Bastian." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180499867/34.
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COSTABILE, FRANCESCA. "Development of an in vitro murine three-dimensional tumor model to study the micro-environment ability to tune cell’s features." Doctoral thesis, Università degli studi di Genova, 2022. http://hdl.handle.net/11567/1079876.
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Background: The tumor microenvironment (TME) is a complex system, shaped by direct interactions among different cell types and by the interactions between cells and extracellular matrix (ECM). Given the emerging importance of the TME in modulating cells’ morphology and function, more sophisticated tumor models incorporating TME features are needed to elucidate cellular, molecular, and immunologic mechanisms of tumor response or resistance. An intensive investigation of in vitro models able to study tumor biology has led to the generation of different three-dimensional (3D) culture methods that better mimic in vivo conditions compared to the usual 2D culture methods. The 3D mono- and co-cultures are able to reproduce some “in vivo features” such as 3D cell morphology, which permits cells to better execute their function and enables them to deposit significant increased amount of ECM.
Aim of this study is the development of an accurate in vitro 3D tumor model to study the impact of tumor ECM on the cells of the microenvironment. The understanding of the specific contributions that ECM proteins make to the tumor microenvironment became crucial due to the emergency of find alternative cures to the many cancer harboring patients resistant to the existing therapies.
Methods: Our experimental approach can be divided in two main experimental plans:
• the development of tumor spheroid model, helpful to understand the beginning stage of the nascent tumor; at day 7, 14 and 21 of spheroids culture we evaluated ECM deposition through immunofluorescence (IF) analysis of collagen type VI; we also analyzed how much the 3D co-culture model we generated was similar compared to the in vivo microenvironment regarding gene expression;
• the development of a scaffold obtained by murine tumor tissue decellularization, utilized for the study of the advanced tumor stage, with a more complex ECM compared to the spheroid model; some scaffolds underwent to collagen type VI IF analysis while other scaffolds were used for recellularization experiments with B16f10 or NIH/3T3 cell lines. Some scaffolds were also used for scanning electron microscopy analysis (SEM).
Results and Discussion: Spheroids generated by the co-culture of B16f10 and NIH/3T3 cells were the only ones lasting for 21 days and the only ones where collagen type VI was detected, compared to spheroids made just by B16f10. These results let us deduce that ECM deposition is fibroblast-dependent. According to the 3D morphology classification of Kenny et al. 2007, B16f10 + NIH/3T3 derived spheroids we generated belong to the Mass class, characterized by cells organized in a regular manner around the center of the colony; B16f10 derived spheroids seems to belong instead to the Grape-like class, characterized by colonies with poor cell-cell contacts and distinguished by their grape-like appearance. B16f10-spheroid’s morphology clearly show a lack of robust cell-cell adhesion, result that has to be overlapped with the absence of collagen type VI. Therefore, fibroblasts are needed for the generation of an early tumor stage 3D model because of their major role as ECM producers and tumor micro-environment organizers. We even investigated spheroid gene expression signature. We focused on the genes that were expressed at the same level between the tumor cells derived from the 3D coculture and the actual in vivo tumor microenvironment. Clusters analysis highlights the similarity between the 2 groups showing 23.1% of the found pathways referring to cancer microenvironment, giving grand importance to the spheroid as in vitro model compared to the 2D systems.
To define an in vitro 3D model suitable to the experimentation on advanced solid tumor phase, murine B16f10 derived tumors were processed for decellularization and studied to verify the efficacy as a natural scaffold for 3D culture system. As observed also from other research groups, cell attachment was limited to the border of the tissue, and it seems cells were not able to pass through the ECM. Control experiment with polyurethane demonstrate the capability of cells to infiltrate a synthetic matrix. To have a better understanding of the ECM structure, frozen sections of decellularized tissue were analyzed by confocal microscope for detection of collagen type VI. Interestingly, both immunofluorescence and histochemistry analysis showed an increase of ECM in decellularized tissue compared to the not decellularized one. This may be due to a slight collapse of the tumor structure since cells have been removed from it. We implemented the ECM observation with the support of SEM: after the decellularization treatment the extracellular fibres are exposed and as hypothesized, the lack of cells makes the fibres twist on themselves, generating a complex net, probably impenetrable from cells. To create a method to measure the collapse of the extracellular matrix that a decellularization treatment may provokes, we compared a fresh and a decellularized specimen of mouse pulmonary parenchyma, where structural modifications are easy to be detected. In this way we were able to quantify the collapse of the ECM through alveoli area reduction.
Conclusions: The development of the spheroid made by tumor and fibroblast cells is a more realistic environment compared to the usual 2D culture and to the spheroid made simply by tumor cells. Fibroblasts are needed for the generation of a better 3D model because of their major role as ECM producers and tumor micro-environment organizers. The limit of the spheroid model is the time, since, to date, the system does not provide oxygen import, necessary for the tumor bulk growth. Tumor derived 3D scaffolds by decellularization most truthfully represents the real in vivo scenario of a tumor 3D model, but the recellularization lack is very often a big limit. Our data demonstrate that the decellularizzation process provokes the collapse of the matrix that does not allow the tissue to be utilized as scaffold for in vitro cell experimentation. Here we also provide, for the first time, a method to test the damage that the treatment provokes on the samples, avoiding the loss of precious materials.
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Le, Cornet Charlotte. "Évolution du cancer du testicule en Europe : expositions environnementales et professionnelles." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10277/document.
Full textAbstract:
Les tumeurs germinales du testicule (TGT) représentent le cancer le plus fréquent chez les hommes Européens âgés de 15 et 39 ans. L'incidence a doublé dans la plupart des pays Européens depuis 30 ans. Cette augmentation rapide, les variations géographiques d'incidence et les études chez les populations migrantes suggèrent un rôle des facteurs environnementaux dans le développement des TGT. Cette thèse propose de contribuer à l'amélioration des connaissances concernant l'évolution du TGT en clarifiant l'impact des expositions environnementales et professionnelles, notamment pendant la période prénatale. Les objectifs principaux sont de: 1. Prédire l'incidence du TGT jusqu'en 2025 en estimant la part d'augmentation due aux changements démographiques afin d'obtenir une estimation de l'augmentation due aux risques. 2. Faire un bilan de l'état des connaissances sur l'association entre les expositions environnementales et professionnelles et le développement du TGT dans une revue systématique de littérature 3. Investiguer l'association entre l'exposition parentale professionnelle aux pesticides en période prénatale et le TGT parmi la descendance Les résultats montrent que l'incidence du TGT continue d'augmenter, mettant en avant un fort impact environnemental dans l'évolution du TGT. Néanmoins, la revue de littérature ne permettait pas d'identifier de facteurs de risque environnementaux avérés, mais montrait un manque d'études investiguant les expositions prénatales sur le risque de TGT. L'étude NORD-TEST menée sur les données de registre de quatre pays nordiques est l'étude la plus puissante à ce jour et ne montre aucune association entre l'exposition parentale professionnelle aux pesticides en période prénatale et le TGTTesticular germ cell tumours (TGCT) are the most common cancer diagnosed among young European men aged between 15 and 39 years. TGCT incidence rates have doubled in most European countries over the last 30 years. This rapid increase in incidence, the geographical variations and the studies in migrant populations suggest a role of environmental factors in TGCT aetiology. This thesis aims to contribute to the knowledge of TGCT evolution by studying the impact of environmental and occupational exposures, especially during the prenatal period. The objectives are: 1. To estimate the proportion of the increased incidence due to overall changes in risk patterns compared to the proportion due to demographic changes, by predicting the future testicular cancer trends in Europe 2. To summarize and evaluate the current knowledge on environmental and occupational exposures related to TGCT risk by means of a systematic literature review 3. To investigate the association between the prenatal parental occupational exposure to pesticides and TGCT risk in the offspring. The results show that the TGCT incidence continues to increase, supporting an environmental impact on TGCT evolution. From the epidemiological literature to date no specific environmental risk factors emerge; however, there have clearly been a lack of studies investigating prenatal exposures on TGCT risk. The NORD-TEST study, based on registry data from four Nordic countries, is the largest study to date. No association was found between parental occupational exposure to pesticides during prenatal period and TGCT risk
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Luna, Brenda. "Prenatal Environmental Exposure and Neurodevelopmentally Important Gene Expression in Malformed Brain Tissue from Pediatric Intractable Epilepsy Patients." FIU Digital Commons, 2011. http://digitalcommons.fiu.edu/etd/445.
Full textAbstract:
The primary objective of this proposal was to determine whether mitochondrial oxidative stress and variation in a particular mtDNA lineage contribute to the risk of developing cortical dysplasia and are potential contributing factors in epileptogenesis in children. The occurrence of epilepsy in children is highly associated with malformations of cortical development (MCD). It appears that MCD might arise from developmental errors due to environmental exposures in combination with inherited variation in response to environmental exposures and mitochondrial function. Therefore, it is postulated that variation in a particular mtDNA lineage of children contributes to the effects of mitochondrial DNA damage on MCD phenotype. Quantitative PCR and dot blot were used to examine mitochondrial oxidative damage and single nucleotide polymorphism (SNP) in the mitochondrial genome in brain tissue from 48 pediatric intractable epilepsy patients from Miami Children’s Hospital and 11 control samples from NICHD Brain and Tissue Bank for Developmental Disorders.
Epilepsy patients showed higher mtDNA copy number compared to normal health subjects (controls). Oxidative mtDNA damage was lower in non-neoplastic but higher in neoplastic epilepsy patients compared to controls. There was a trend of lower mtDNA oxidative damage in the non-neoplastic (MCD) patients compared to controls, yet, the reverse was observed in neoplastic (MCD and Non-MCD) epilepsy patients. The presence of mtDNA SNP and haplogroups did not show any statistically significant relationships with epilepsy phenotypes. However, SNPs G9804A and G9952A were found in higher frequencies in epilepsy samples. Logistic regression analysis showed no relationship between mtDNA oxidative stress, mtDNA copy number, mitochondrial haplogroups and SNP variations with epilepsy in pediatric patients. The levels of mtDNA copy number and oxidative mtDNA damage and the SNPs G9952A and T10010C predicted neoplastic epilepsy, however, this was not significant due to a small sample size of pediatric subjects. Findings of this study indicate that an increase in mtDNA content may be compensatory mechanisms for defective mitochondria in intractable epilepsy and brain tumor. Further validation of these findings related to mitochondrial genotypes and mitochondrial dysfunction in pediatric epilepsy and MCD may lay the ground for the development of new therapies and prevention strategies during embryogenesis.
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Van, Woensel Matthias. "Sensitization of glioblastoma tumor micro-environment to chemo- and immunotherapy by Galectin-1 reduction after intranasal anti-Gal-1 siRNA administration." Doctoral thesis, Universite Libre de Bruxelles, 2016. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/240945.
Full textAbstract:
High grade gliomas remain a devastating disease, for which a curative therapy is virtually absent. The high medical need is unmet by novel treatment strategies and advances in chemo-and radiotherapy. Patients diagnosed for GBM face a median survival of 15 months after maximal standard-of-care therapy, and relapse is often observed due to micro-metastasis in the direct environment of resection. In part, current treatment modalities such as chemo-and immunotherapy are hampered in their efficacy due to the specialized TME. This area is adequately equipped to withstand the cytotoxic attack of chemo- and immunotherapy. Therefore, we hypothesized that modulation of the TME could decrease these defense mechanisms, and increase susceptibility to tumor lysis.In this respect, we focused on Gal-1 as an ideal target to modulate the TME in the context of GBM. Gal-1 exerts multiple tumor promoting functions. From pre-clinical research, we have learned that Gal-1 is an important mediator for the proliferation and migration of tumor cells, moreover Gal-1 could also promote angiogenesis in the TME, providing nutrients and oxygen for GBM to grow. Gal-1 also maintains the inherent defense mechanisms to chemo and immunotherapy. Gal-1 is crucial for the resistance mechanisms to TMZ by altering the EPR stress response. Moreover, and most important for our purposes, Gal-1 is also a crucial immune suppressor in the TME, which can induce apoptosis in activated T cells, and recruit Tregs. To target Gal-1 in the TME would be clinically most relevant if this could be performed via a non-invasive treatment modality. Therefore, we developed a nanoparticle complex that could deliver siGal-1 from the nasal cavity directly to the CNS, and even the TME. This nose-to-brain delivery bypasses systemic routes, with a higher (and more selective) local bioavailability in the CNS. The major pharmaceutical excipient in this nanoparticle complex consists of chitosan polymers. These polymers are highly interesting agents to promote nose-to-brain delivery due their muco-adhesive and epithelial barrier modulation properties. When applying these particles in vitro on GBM cells, a solid decrease of Gal-1 was noted, and the epithelial modulatory properties were confirmed. Furthermore, we observed a rapid transport from the nasal cavity to the brain upon intranasal administration of a highly-concentrated chitosan nanoparticle siGal-1 suspension and we could even observe the sequence-specific cleavage of Gal-1 mRNA, and a decrease of Gal-1 in the TME. This Gal-1 reduction could modulate the TME from immune suppression to immune activation, as demonstrated by decrease in suppressor cells, and increased stage of activation in rejective immune cells. Moreover, due to decreased Gal-1, also angiogenesis was alleviated, and a reduced size in vasculature was observed, mimicking a morphological vessel normalisation. Reversing the immune and vascular contexture of the TME by Gal-1 reduction seemed a prerequisite to increase the efficacy of TMZ, DC vaccination and PD-1 blocking. In combination experiments, we noticed that siGal-1 on top of these treatments, could further increase the efficiency of chemo and immunotherapy. The findings presented in this thesis can serve as a proof of concept for the feasibility to modulate and re-orchestrate the TME of GBM via intranasal administration. The intranasal administration of siGal-1 could represent a valuable clinically translational treatment to increase the efficiency of chemo- and immunotherapy for GBM patients. In our research facilities, a phase 0 as a first-in-human trial is actively pursued.Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie)
info:eu-repo/semantics/nonPublished
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RUGGIERI, ELENA. "Discovery of HMGB1 recycling as a novel rheostat in muscle regeneration and tumor microenvironment." Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/133068.
Full textAbstract:
High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear protein that is released by injured cells to serve a soluble message of tissue damage and to trigger inflammation and tissue regeneration. The regenerative properties of HMGB1 have been investigated in multiple tissues and organs, especially in skeletal muscle in which HMGB1 appears to be a limiting factor in physiological conditions. To identify the source(s) of HMGB1 during muscle repair, we generated conditional HMGB1 knockout mouse models with specific deletion in myogenic cells, endothelial cells or platelets. We found that HMGB1 mainly derives from non-muscle cells in injured muscle. Interestingly, there were distinct delays in the regenerative process in the different cell-specific HMGB1 KO mice, indicating that HMGB1 derived from different sources plays distinct roles in muscle regeneration and that a timely and spatially regulated release of HMGB1 is required for optimal regeneration. To further emphasize the importance of HMGB1 in the regeneration process, we generated a whole body inducible HMGB1 KO mouse model. As expected, we observed a severe impairment in muscle regeneration, and more specifically a delay in leucocyte recruitment, confirming the crucial role of HMGB1 in this process. Apart from rare studies mainly focused on macrophages, the fate of HMGB1 after release in the extracellular environment remains largely unexplored. This is a key question because a tight regulation of HMGB1 extracellular level is essential to support tissue regeneration but also to avoid detrimental effects such as persistent inflammation. We uncovered HMGB1 internalization, as a mechanism of recycling during skeletal muscle regeneration, that appears to be important for the control of myofiber size. Similarly, we observed HMGB1 recycling in the tumor microenvironment and preliminary data indicate that this process might contribute to DNA repair in response to radiotherapy. We identified heparan sulfate proteoglycans as mediators of HMGB1 internalization, and more specifically syndecan-4. In conclusion, our findings further emphasize the importance of HMGB1 in the regeneration process and unraveled its internalization as a mechanism of recycling in injured muscle and tumor microenvironment. This protein-saving process might play pivotal roles in tissue regeneration as well as in cancer progression and, more generally, in many physiological and pathological conditions in which the contribution of HMGB1 has been reported.High Mobility Group Box 1 (HMGB1) è una proteina nucleare ubiquitaria che viene rilasciata dalle cellule danneggiate per fornire un messaggio di danno tissutale e per attivare l'infiammazione e la rigenerazione dei tessuti. Le proprietà rigenerative di HMGB1 sono state studiate in molteplici tessuti e organi, in particolare nel muscolo scheletrico in cui HMGB1 sembra essere un fattore limitante in condizioni fisiologiche. Per identificare la fonte di HMGB1 durante la riparazione muscolare, abbiamo generato modelli murini deleti per HMGB1 specificamente in cellule miogeniche, cellule endoteliali o piastrine. Abbiamo scoperto che HMGB1 deriva principalmente da cellule non muscolari nel muscolo danneggiato. È interessante notare che ci sono stati ritardi diversi nel processo rigenerativo nei diversi topi HMGB1 specifici per le diverse cellule, questo suggerisce che HMGB1 derivato da fonti diverse svolge ruoli distinti nella rigenerazione muscolare e che è necessario un rilascio tempestivo e regolato di HMGB1 per una rigenerazione ottimale. Per sottolineare ulteriormente l'importanza di HMGB1 nel processo di rigenerazione, abbiamo generato un modello di topo deleto di HMGB1 in tutto il corpo. Come previsto, abbiamo osservato una grave compromissione della rigenerazione muscolare e, più specificamente, un ritardo nel reclutamento dei leucociti, confermando il ruolo cruciale di HMGB1 in questo processo. A parte rari studi incentrati principalmente sui macrofagi, il destino di HMGB1 dopo il rilascio nell'ambiente extracellulare rimane in gran parte inesplorato. Questa è una domanda chiave perché un’accurata regolazione del livello extracellulare di HMGB1 è essenziale per supportare la rigenerazione dei tessuti ma anche per evitare effetti dannosi come l'infiammazione persistente. Abbiamo scoperto l'interiorizzazione di HMGB1, come meccanismo di riciclo durante la rigenerazione del muscolo scheletrico, che sembra essere importante per il controllo delle dimensioni delle miofibre. Allo stesso modo, abbiamo osservato il riciclo di HMGB1 nel microambiente tumorale e i dati preliminari indicano che questo processo potrebbe contribuire alla riparazione del DNA in risposta alla radioterapia. Abbiamo identificato gli eparan solfati come mediatori dell'internalizzazione di HMGB1 e più specificamente syndecan-4. In conclusione, i nostri risultati sottolineano ulteriormente l'importanza di HMGB1 nel processo di rigenerazione e hanno svelato la sua internalizzazione come meccanismo di riciclo nel muscolo danneggiato e nel microambiente tumorale. Questo processo di risparmio proteico potrebbe svolgere un ruolo fondamentale nella rigenerazione dei tessuti così come nella progressione del cancro e, più in generale, in molte condizioni fisiologiche e patologiche in cui è stato riportato il contributo di HMGB1.
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RUGGIERI, ELENA. "Discovery of HMGB1 recycling as a novel rheostat in muscle regeneration and tumor microenvironment." Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/133067.
Full textAbstract:
High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear protein that is released by injured cells to serve a soluble message of tissue damage and to trigger inflammation and tissue regeneration. The regenerative properties of HMGB1 have been investigated in multiple tissues and organs, especially in skeletal muscle in which HMGB1 appears to be a limiting factor in physiological conditions. To identify the source(s) of HMGB1 during muscle repair, we generated conditional HMGB1 knockout mouse models with specific deletion in myogenic cells, endothelial cells or platelets. We found that HMGB1 mainly derives from non-muscle cells in injured muscle. Interestingly, there were distinct delays in the regenerative process in the different cell-specific HMGB1 KO mice, indicating that HMGB1 derived from different sources plays distinct roles in muscle regeneration and that a timely and spatially regulated release of HMGB1 is required for optimal regeneration. To further emphasize the importance of HMGB1 in the regeneration process, we generated a whole body inducible HMGB1 KO mouse model. As expected, we observed a severe impairment in muscle regeneration, and more specifically a delay in leucocyte recruitment, confirming the crucial role of HMGB1 in this process. Apart from rare studies mainly focused on macrophages, the fate of HMGB1 after release in the extracellular environment remains largely unexplored. This is a key question because a tight regulation of HMGB1 extracellular level is essential to support tissue regeneration but also to avoid detrimental effects such as persistent inflammation. We uncovered HMGB1 internalization, as a mechanism of recycling during skeletal muscle regeneration, that appears to be important for the control of myofiber size. Similarly, we observed HMGB1 recycling in the tumor microenvironment and preliminary data indicate that this process might contribute to DNA repair in response to radiotherapy. We identified heparan sulfate proteoglycans as mediators of HMGB1 internalization, and more specifically syndecan-4. In conclusion, our findings further emphasize the importance of HMGB1 in the regeneration process and unraveled its internalization as a mechanism of recycling in injured muscle and tumor microenvironment. This protein-saving process might play pivotal roles in tissue regeneration as well as in cancer progression and, more generally, in many physiological and pathological conditions in which the contribution of HMGB1 has been reported.High Mobility Group Box 1 (HMGB1) è una proteina nucleare ubiquitaria che viene rilasciata dalle cellule danneggiate per fornire un messaggio di danno tissutale e per attivare l'infiammazione e la rigenerazione dei tessuti. Le proprietà rigenerative di HMGB1 sono state studiate in molteplici tessuti e organi, in particolare nel muscolo scheletrico in cui HMGB1 sembra essere un fattore limitante in condizioni fisiologiche. Per identificare la fonte di HMGB1 durante la riparazione muscolare, abbiamo generato modelli murini deleti per HMGB1 specificamente in cellule miogeniche, cellule endoteliali o piastrine. Abbiamo scoperto che HMGB1 deriva principalmente da cellule non muscolari nel muscolo danneggiato. È interessante notare che ci sono stati ritardi diversi nel processo rigenerativo nei diversi topi HMGB1 specifici per le diverse cellule, questo suggerisce che HMGB1 derivato da fonti diverse svolge ruoli distinti nella rigenerazione muscolare e che è necessario un rilascio tempestivo e regolato di HMGB1 per una rigenerazione ottimale. Per sottolineare ulteriormente l'importanza di HMGB1 nel processo di rigenerazione, abbiamo generato un modello di topo deleto di HMGB1 in tutto il corpo. Come previsto, abbiamo osservato una grave compromissione della rigenerazione muscolare e, più specificamente, un ritardo nel reclutamento dei leucociti, confermando il ruolo cruciale di HMGB1 in questo processo. A parte rari studi incentrati principalmente sui macrofagi, il destino di HMGB1 dopo il rilascio nell'ambiente extracellulare rimane in gran parte inesplorato. Questa è una domanda chiave perché un’accurata regolazione del livello extracellulare di HMGB1 è essenziale per supportare la rigenerazione dei tessuti ma anche per evitare effetti dannosi come l'infiammazione persistente. Abbiamo scoperto l'interiorizzazione di HMGB1, come meccanismo di riciclo durante la rigenerazione del muscolo scheletrico, che sembra essere importante per il controllo delle dimensioni delle miofibre. Allo stesso modo, abbiamo osservato il riciclo di HMGB1 nel microambiente tumorale e i dati preliminari indicano che questo processo potrebbe contribuire alla riparazione del DNA in risposta alla radioterapia. Abbiamo identificato gli eparan solfati come mediatori dell'internalizzazione di HMGB1 e più specificamente syndecan-4. In conclusione, i nostri risultati sottolineano ulteriormente l'importanza di HMGB1 nel processo di rigenerazione e hanno svelato la sua internalizzazione come meccanismo di riciclo nel muscolo danneggiato e nel microambiente tumorale. Questo processo di risparmio proteico potrebbe svolgere un ruolo fondamentale nella rigenerazione dei tessuti così come nella progressione del cancro e, più in generale, in molte condizioni fisiologiche e patologiche in cui è stato riportato il contributo di HMGB1.
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Hollinshead, Katy Elizabeth Rose. "Metabolic rewiring in response to genetic and environmental preturbations in cancer." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6989/.
Full textAbstract:
Cancer cells reprogram their metabolism to supply biosynthetic and bioenergetic demands of rapid proliferation. Microenvironmental changes, such as hypoxia, further influence tumour metabolism, driving malignancy. Recent identification of cancer-associated mutations in succinate dehydrogenase (SDH), fumarate hydratase and isocitrate dehydrogenase (IDH) have shown that genetic alterations can directly alter tumour cell metabolism, and may be required for malignant transformation. Mutations in these metabolic enzymes promote tumorigenesis by hijacking the adaptive response to hypoxia. Understanding the metabolic vulnerabilities associated with these mutations may therefore elicit the design of more selective therapies. Employing a combination of analytical approaches to study metabolism, the research objectives were to characterise metabolic vulnerabilities associated with cells mutated in SDHB and IDH1. Results show that cells deficient in SDH activity maintain proliferation and viability by increasing dependency on pyruvate carboxylase for de novo aspartate synthesis. Mutations in IDH1 have a complex role in the metabolic adaptation to hypoxia, partially compromising this hypoxic response, yet also demonstrating aspects of pseudohypoxia, such as increased proline anabolism. This thesis reveals a metabolic vulnerability that could be therapeutically targeted to treat SDH-mutated tumours, and a novel redox-sensitive metabolic pathway, exhibited by both pseudohypoxic SDH and IDH1 mutated tumours, used to retain metabolic plasticity.
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Kunkle, Brian W. "The Potential Role of Environmental Exposures and Genomic Signaling in Development of Central Nervous System Tumors." FIU Digital Commons, 2011. http://digitalcommons.fiu.edu/etd/524.
Full textAbstract:
The etiology of central nervous system tumors (CNSTs) is mainly unknown. Aside from extremely rare genetic conditions, such as neurofibromatosis and tuberous sclerosis, the only unequivocally identified risk factor is exposure to ionizing radiation, and this explains only a very small fraction of cases. Using meta-analysis, gene networking and bioinformatics methods, this dissertation explored the hypothesis that environmental exposures produce genetic and epigenetic alterations that may be involved in the etiology of CNSTs.
A meta-analysis of epidemiological studies of pesticides and pediatric brain tumors revealed a significantly increased risk of brain tumors among children whose mothers had farm-related exposures during pregnancy. A dose response was recognized when this risk estimate was compared to those for risk of brain tumors from maternal exposure to non-agricultural pesticides during pregnancy, and risk of brain tumors among children exposed to agricultural activities. Through meta-analysis of several microarray studies which compared normal tissue to astrocytomas, we were able to identify a list of 554 genes which were differentially expressed in the majority of astrocytomas. Many of these genes have in fact been implicated in development of astrocytoma, including EGFR, HIF-1α, c-Myc, WNT5A, and IDH3A. Reverse engineering of these 554 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme (GBM) were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. Lastly, bioinformatics analysis of environmental databases and curated published results on GBM was able to identify numerous potential pathways and gene-environment interactions that may play key roles in astrocytoma development.
Findings from this research have strong potential to advance our understanding of the etiology and susceptibility to CNSTs. Validation of our 'key genes' and pathways could potentially lead to useful tools for early detection and novel therapeutic options for these tumors.
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Chaudhuri, Leena. "Manganese superoxide dismutase (MnSOD) 3'-untranslated region: a novel molecular sensor for environmental stress." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/2682.
Full textAbstract:
Eukaryotic gene expression is a complex process and can be controlled at the level of transcription, post-transcription or translation and post-translation. In recent years, there is a growing interest in understanding the role of 3'-untranslated region (UTR) in regulating mRNA turnover and translation. The 3'-UTR harbors the poly(A) signal and post-transcriptional regulatory sequences like miRNA and AU-rich elements (AREs). The presence of multiple poly(A) sites often results in multiple transcripts; shorter transcripts correlating with more protein abundance. Manganese superoxide dismutase (MnSOD) is a nuclear encoded and mitochondrial matrix localized antioxidant enzyme that converts mitochondrial generated superoxide to hydrogen peroxide. Human MnSOD has two poly(A) sites resulting in two transcripts: 1.5 and 4.2 kb. We hypothesize that the 3'-UTR of MnSOD regulates its mRNA and protein levels as well as activity in response to growth states and environmental stress. Results from a Q-RT-PCR assay showed a preferential accumulation of the shorter MnSOD transcript during quiescence, which correlated with an increase in MnSOD activity. The accumulation of the longer MnSOD transcript during proliferation was associated with a decrease in MnSOD activity. Log transformed expression ratio of the longer to shorter transcript was also higher in proliferating epithelial non-cancerous (mammary: MCF-10A) and cancer cells (mammary: MB-231, SUM 159; oral squamous: SQ20B, FaDu, Cal27; and lung: A549, H292), suggesting that the abundance of the longer transcript is independent of cellular transformation status, instead it is dependent on cellular growth state. Interestingly, the abundance of the longer transcript directly correlated with percent S-phase (R2=0.86). The shorter transcript was enriched in irradiated MB-231 cells. MCF-10A cells exposed to 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of the environmental pollutant polychlorinated biphenyl 3, showed a significant decrease in the abundance of the 4.2 kb transcript due to a faster mRNA turnover, 14 h compared to 20 h in untreated control cells. The decrease in the 4.2 kb transcript levels was associated with a corresponding decrease in MnSOD protein levels and activity, which resulted in a significant inhibition of quiescent cells entry into the proliferative cycle. Deletion and reporter assays showed: (a) a significant decrease in reporter activity in constructs carrying multiple AREs that are present in the 3'-UTR of the longer MnSOD transcript; (b) irradiation increased the reporter activity of the constructs carrying the 3'-UTR sequence of the shorter MnSOD transcript and (c) N-acetyl-cysteine increased the reporter activity of constructs carrying multiple AREs. Because the longer transcript carries AREs, our results identified redox sensitive AREs as novel regulators of MnSOD transcript levels. We conclude that MnSOD 3'-UTR is a novel molecular sensor regulating MnSOD mRNA levels in response to different growth states and environmental stress. A better understanding of the 3'-UTR regulating gene expression could lead to the development of new molecular biology-based redox therapy designed to treat proliferative disorders.
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Zhang, Xiaohan [Verfasser], Christine M. [Akademischer Betreuer] Papadakis, Christine M. [Gutachter] Papadakis, and Friedrich C. [Gutachter] Simmel. "Macromolecular pHPMA-Based Nanoparticles for Solid Tumor Targeting: Behavior in Protein Environment / Xiaohan Zhang ; Gutachter: Christine M. Papadakis, Friedrich C. Simmel ; Betreuer: Christine M. Papadakis." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1170321682/34.
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Zhang, Xiaohan Verfasser], Christine M. [Akademischer Betreuer] [Papadakis, Christine M. [Gutachter] Papadakis, and Friedrich C. [Gutachter] Simmel. "Macromolecular pHPMA-Based Nanoparticles for Solid Tumor Targeting: Behavior in Protein Environment / Xiaohan Zhang ; Gutachter: Christine M. Papadakis, Friedrich C. Simmel ; Betreuer: Christine M. Papadakis." München : Universitätsbibliothek der TU München, 2018. http://nbn-resolving.de/urn:nbn:de:bvb:91-diss-20181019-1452340-1-7.
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Sinks, Thomas H. "N-nitroso compounds, pesticides, and parental exposures in the workplace as risk factors for childhood brain cancer : a case-control study /." The Ohio State University, 1985. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487260859497125.
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Moreno, Mendoza Daniel. "Tumor testicular de células germinales: identificación de nuevos factores de riesgo." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/671273.
Full textAbstract:
La present tesi és una aportació a el coneixement de nous factors de risc per al tumor testicular de cèl·lules germinals (TTCG). El TTCG presenta una etiologia multifactorial, atribuïble a un retard en la diferenciació dels gonocitos fetals. El TTCG és més freqüent en homes amb una espermatogènesi alterada, suggerint una possible etiopatogènia comuna. El cromosoma I conté gens essencials per a una correcta espermatogènesi, les regions de l'factor d'azoospèrmia (AZF). La regió AZF més dinàmica és la regió AZFc que presenta punts fràgils que predisposa a reordenaments. El reordenament parcial més rellevant des del punt de vista clínic de la regió AZFc és la deleció gr / gr. S'ha relacionat la delació gr / gr amb un major risc de desenvolupar un TTCG, però la falta d'informació sobre els paràmetres seminals dels pacients no ha permès d'aclarir si l'associació observada està relacionada amb l'espermatogènesi alterada o si és un factor de risc independent. A més, encara queda per establir si altres tipus de delecions i duplicacions de la regió AZFc presenten relació amb el TTCG. La primera part d'aquesta tesi s'enfoca en l'estudi dels reordenaments parcials de la regió AZFc al TTCG. S'han analitzat 497 pacients amb TTCG i 2030 controls sense TTCG. Un 3.8% dels pacients amb TTCG presentaven algun tipus de deleció parcial de la regió AZFc respecte a l'2.5% de el grup control (p = 0.078). La deleció parcial més freqüent va ser la deleció gr / gr, mentre que els altres tipus de delecions parcials de la regió AZFc van resultar ser molt rares. Segons el fenotip seminal, es va observar un major risc de TTCG en pacients normozoospérmicos portadors de delecions parcials de la regió AZFc respecte als controls normozoospérmicos. No hi va haver diferències significatives entre pacients i controls segons les duplicacions parcials de la regió AZFc. Es va mostrar que les alteracions en la dosi de el gen DAZ confereixen un major risc de TTCG.
Aquests resultats confirmen que un dèficit de l'contingut gènic de la regió AZFc juga un paper important en la etiopatogènesi de l'TTCG. En particular, la deleció gr / gr confereix un risc significatiu per al desenvolupament de l'TTCG independentment dels paràmetres seminals.
Els factors ambientals també estan involucrats en la etiopatogènesi de l'TTCG, especialment si interfereixen en un període específic de el desenvolupament testicular, en el denominat ""masculinization programming window"" (MPW). Un desequilibri hormonal en aquest període compromet a la correcta funció de les cèl·lules fetals de Sertoli i Leydig, originant la síndrome de disgenèsia testicular (SDT).
La distància anogenital (DAG) és considerada un biomarcador de l'acció dels andrògens durant el MPW. La DAG més curta ha estat relacionada amb tots els components de l'SDT, excepte amb el TTCG.
La segona part d'aquesta tesi valora l'associació entre la DAG i el TTCG. A més avalua el paper de l'polimorfisme CAG de el gen AR en el desenvolupament de l'TTCG i la DAG. Es van analitzar a 156 pacients amb TTCG i 110 controls sans normozoospérmicos. Es va observar una distància anopeneana (DAGap) i una distància anoescrotal (dagues) significativament més curta en els TTCG respecte als controls. Es van definir uns punt de tall (DAGap: 130mm; dagues: 53mm) que indiquen un major risc de TTCG en aquells individus que es trobin per sota d'aquests valors. No s'ha trobat relació entre el polimorfisme CAG i el TTCG o la longitud de la DAG.
En conclusió, les dades revelen que els pacients amb una DAG més curta presenten un major risc de TTCG, recolzant la teoria sobre la influència de l'desequilibri androgènic durant el desenvolupament fetal en l'etiopatogènia de l'TTCG.La presente tesis es una aportación al conocimiento de nuevos factores de riesgo para el tumor testicular de células germinales (TTCG). El TTCG presenta una etiología multifactorial, atribuible a un retraso en la diferenciación de los gonocitos fetales. El TTCG es más frecuente en varones con una espermatogénesis alterada, sugiriendo una posible etiopatogenia común. El cromosoma Y contiene genes esenciales para una correcta espermatogénesis, las regiones del factor de azoospermia (AZF). La región AZF más dinámica es la región AZFc que presenta puntos frágiles que predispone a reordenamientos. El reordenamiento parcial más relevante desde el punto de vista clínico de la región AZFc es la deleción gr/gr. Se ha relacionado la delación gr/gr con un mayor riesgo de desarrollar un TTCG, pero la falta de información sobre los parámetros seminales de los pacientes no ha permitido de clarificar si la asociación observada está relacionada con la espermatogénesis alterada o si es un factor de riesgo independiente. Además, aún queda por establecer si otros tipos de deleciones y duplicaciones de la región AZFc presentan relación con el TTCG. La primera parte de esta tesis se enfoca en el estudio de los reordenamientos parciales de la región AZFc en el TTCG. Se han analizado 497 pacientes con TTCG y 2030 controles sin TTCG. Un 3.8% de los pacientes con TTCG presentaban algún tipo de deleción parcial de la región AZFc respecto al 2.5% del grupo control (p= 0.078). La deleción parcial más frecuente fue la deleción gr/gr, mientras que los otros tipos de deleciones parciales de la región AZFc resultaron ser muy raras. Según el fenotipo seminal, se observó un mayor riesgo de TTCG en pacientes normozoospérmicos portadores de deleciones parciales de la región AZFc respecto a los controles normozoospérmicos. No hubo diferencias significativas entre pacientes y controles según las duplicaciones parciales de la región AZFc. Se mostró que las alteraciones en la dosis del gen DAZ confieren un mayor riesgo de TTCG. Estos resultados confirman que un déficit del contenido génico de la región AZFc juega un papel importante en la etiopatogénesis del TTCG. En particular, la deleción gr/gr confiere un riesgo significativo para el desarrollo del TTCG independientemente de los parámetros seminales. Los factores ambientales también están involucrados en la etiopatogénesis del TTCG, especialmente si interfieren en un periodo específico del desarrollo testicular, en el denominado "masculinization programming window" (MPW). Un desequilibrio hormonal en este periodo compromete la correcta función de las células fetales de Sertoli y Leydig, originando el síndrome de disgenesia testicular (SDT). La distancia anogenital (DAG) es considerada un biomarcador de la acción de los andrógenos durante el MPW. La DAG más corta ha sido relacionada con todos los componentes del SDT, excepto con el TTCG. La segunda parte de esta tesis valora la asociación entre la DAG y el TTCG. Además evalúa el papel del polimorfismo CAG del gen AR en el desarrollo del TTCG y la DAG. Se analizaron a 156 pacientes con TTCG y 110 controles sanos normozoospérmicos. Se observó una distancia anopeneana (DAGap) y una distancia anoescrotal (DAGas) significativamente más corta en los TTCG respecto a los controles. Se definieron unos punto de corte (DAGap: 130mm ;DAGas: 53mm) que indican un mayor riesgo de TTCG en aquellos individuos que se encuentren por debajo de estos valores. No se encontró relación entre el polimorfismo CAG y el TTCG o la longitud de la DAG. En conclusión, los datos revelan que los pacientes con una DAG más corta presentan un mayor riesgo de TTCG, apoyando la teoría sobre la influencia del desequilibrio androgénico durante el desarrollo fetal en la etiopatogenia del TTCG.
This thesis is a contribution to the knowledge of new risk factors for testicular germ cell tumor (TTCG). TTCG has a multifactorial etiology, attributable to a delay in the differentiation of fetal gonocytes. TTCG is more frequent in men with altered spermatogenesis, suggesting a possible common etiopathogenesis. The Y chromosome contains essential genes for correct spermatogenesis, the azoospermia factor (AZF) regions. The most dynamic AZF region is the AZFc region that presents fragile points that predispose to rearrangements. The most clinically relevant partial rearrangement of the AZFc region is the gr / gr deletion. gr / gr cheating has been associated with an increased risk of developing TTCG, but the lack of information on the seminal parameters of the patients has not made it possible to clarify whether the observed association is related to altered spermatogenesis or if it is a factor of independent risk. Furthermore, it remains to be established whether other types of deletions and duplications of the AZFc region are related to TTCG. The first part of this thesis focuses on the study of partial rearrangements of the AZFc region in the TTCG. 497 patients with TTCG and 2030 controls without TTCG have been analyzed. 3.8% of the patients with TTCG presented some type of partial deletion of the AZFc region compared to 2.5% of the control group (p = 0.078). The most frequent partial deletion was the gr / gr deletion, while the other types of partial deletions of the AZFc region were found to be very rare. According to the seminal phenotype, a higher risk of TTCG was observed in normozoospermic patients carrying partial deletions of the AZFc region compared to normozoospermic controls. There were no significant differences between patients and controls according to the partial duplications of the AZFc region. Alterations in the dose of the DAZ gene were shown to confer an increased risk These results confirm that a deficit in the gene content of the AZFc region plays an important role in the etiopathogenesis of TTCG. In particular, the gr / gr deletion confers a significant risk for the development of TTCG regardless of seminal parameters. Environmental factors are also involved in the aetiopathogenesis of TTCG, especially if they interfere in a specific period of testicular development, in the so-called "masculinization programming window" (MPW). A hormonal imbalance in this period compromises the correct function of the fetal Sertoli and Leydig cells, causing the testicular dysgenesis syndrome (TDS). The anogenital distance (DAG) is considered a biomarker of the action of androgens during MPW. The shorter DAG has been related to all components of the SDT, except the TTCG. The second part of this thesis assesses the association between the DAG and the TTCG. It also evaluates the role of the CAG polymorphism of the AR gene in the development of TTCG and DAG. 156 patients with TTCG and 110 healthy normozoospermic controls were analyzed. A significantly shorter anopeneal distance (DAGap) and anoscrotal distance (DAGas) were observed in TTCG compared to controls. Cut-off points were defined (DAGap: 130mm; DAGas: 53mm) that indicate a greater risk of TTCG in those individuals who are below these values. No relationship was found between the CAG polymorphism and the TTCG or the length of the DAG. In conclusion, the data reveal that patients with a shorter DAG have a higher risk of TTCG, supporting the theory about the influence of androgen imbalance during fetal development on the etiopathogenesis of TTCG.
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Arikatla, Swetha. "Effect of Tumor Microenvironmental Conditions on Non Small Cell Lung Cancer." Scholarly Commons, 2017. https://scholarlycommons.pacific.edu/uop_etds/126.
Full textAbstract:
Tumor microenvironmental conditions play a vital role in promoting metastasis and tumor recurrence. Due to inefficient vasculature, cancer cells experience hypoxia, glucose deprivation and low pH even during the early stages of tumor growth. Tumor cells are proposed to adapt to these microenvironmental conditions by acquiring increased migratory and invasion potential and tumor initiating ability. Our research addresses the effect of these biochemical factors of the tumor microenvironment (TME) on motility, epithelial to mesenchymal transition (EMT) and stemness of non-small cell lung cancer (NSCLC). NCI-H292 and NCI-H1650 NSCLC cell lines were used to measure the effect of the above mentioned TME conditions. Apart from acidic pH, low glucose and hypoxia, the effect of high glucose conditions was also measured on H292 and H1650 cell lines. Acidic pH, high and low glucose conditions were observed to have no effect on the motility, EMT and stemness of H1650 cell line. Hence, use of this cell line was discontinued and no further treatment conditions were tested on this cell line. In H292 cell line, acidic pH, low glucose and tumor like conditions combined together (acidic pH + low glucose + hypoxia) [AP+LG+HYP] significantly decreased motility whereas hypoxia significantly increased the motility of H292 cells. High glucose did not affect the motility of H292 cells. Although N-cadherin, a mesenchymal marker, expression was significantly upregulated by acidic pH, high and low glucose conditions, no direct correlation was observed between N-cadherin expression and motility. E-cadherin expression was not affected by acidic pH, high and low glucose conditions. An increase in N-cadherin expression and no change in E-cadherin expression under these conditions might be an indication of partial EMT. Hypoxia and AP+LG+HYP did not alter the expression of E-cadherin and N-cadherin. Although expression of vimentin, another mesenchymal marker, and Sox2, a cancer stem cell marker (CSC), was observed at the mRNA level, no expression of vimentin and Sox2 proteins was observed in H292 cells under any of these treatment conditions. The expression of OCT4, another CSC marker, was also not observed at the protein level in H292 cells. HIF-1α expression was observed in H292 cells under normoxic conditions and was unaffected by hypoxia and AP+LG+HYP. Therefore our research indicates that the effect of these TME conditions might be different on different cancer cell lines or cancer types. Not all cancers may depend on EMT for metastasis. An increase in metastasis under hypoxia may be independent of HIF-1α.
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Castro, Giner Francesc. "Genetic and environmental factors in asthma: a population based European study." Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/7194.
Full textAbstract:
L'asma és una malaltia d'etiologia complexa, formada per factors genètics i ambientals, on la interrelació de ambdós factors mitjançant interaccions gen-ambient juga un paper clau. L'objectiu d'aquesta tesi ha sigut aprofundir en el coneixement del paper dels polimorfismes genètics, i la seva interacció amb factors ambientals, en la ocurrència d'asma, atòpia i hiperreactivitat bronquial. Aquest objectiu ha estat desenvolupat a través de la replicació de variants genètiques prèviament identificades, l'avaluació d'interaccions gen-ambient i la identificació de nous gens de susceptibilitat mitjançant un disseny basat en el genotipatge de variants genètiques all llarg del genoma en pools d'ADN. La tesi ha estat majoritàriament duta a terme dins l'estudi European Community Respiratory Health Survey (ECRHS) que està comprès per 5.000 individus seguits durant 9 anys, pels quals es disposa d'un qüestionari complet sobre símptomes respiratoris, avaluacions clíniques, informació sobre exposicions ambientals i mostres de ADN. Aquesta tesi a replicat l'associació del polimorfismes dels gens TNFA i NPSR1 amb asma. A més s'han establert les interaccions entre TNFA i obesitat, NQO1 i contaminació atmosfèrica, i NPSR1 i edat d'inici d'asma. L'anàlisi de pools d' ADN ha permès associar la regió on es situa el gen SGK493 amb atòpia. Aquesta tesi contribueix al coneixement de l'etiologia d'asma amb la identificació i replicació d'associacions genètiques i interaccions gen-ambient.Asthma is a disease with a complex etiology, involving multiple genetic and environmental factors, and with an important role of the interplay of these factors through gene-environment interactions. In this thesis I aimed to advance our knowledge on the importance of genetic polymorphisms and their interaction with environmental data for the occurrence of asthma and related phenotypes (atopy and bronchial hyperreactivity). This objective was developed through the replication of genetic associations previously reported, the assessment of gene-environment interactions and the identification of new susceptibility genes using genome-wide analysis based on a pooling DNA strategy. The thesis was, mostly, performed within the European Community Respiratory Health Survey (ECRHS). This cohort has information and DNA samples from approximately 5,000 adult subjects followed-up for 9 years, with extensive questionnaires on respiratory symptoms, clinical evaluations and information on environmental exposures. This thesis replicates previous effects on asthma of polymorphisms in TNFA and NPSR1 genes. In addition, interactions have been established between TNFA and obesity, NQO1 and air-pollution, and NPSR1 and age at onset of asthma. The approach based on genome-wide analysis of DNA pools identified the SGK493 region being associated with atopy. This thesis contributes to the understanding of the etiology of asthma through the identification and replication of genetic associations and gene-environment interactions.