The aim of this study was to scrutinize the existing barriers within psychosocial cancer care, through the cancer centers point of view. A literature review was conducted, resulting in ten peer-reviewed articles, to further investigate the psychosocial cancer care in the Western part of the world by assessing existing barriers to effective psychosocial work, and improvements needed for cancer centers to be able to offer aqequate care to patients and their loved ones. The result of the study was divided into sub-themes and revealed four main barriers: Lack of routines and structure within the psychosocial cancer care; ; Lack of understanding and knowledge of the importance of psychosocial work in cancer care among medical staff; Inadequate resources to carry out psychosocial work in terms of Lack of time, staff and economy; and lastly; Lack of access to and understanding of the importance of culture specific and multilingual cancer care. The result of the study was analyzed bearing reference to Michael Lipskys theory of street-level bureaucracy. It appears that the psychosocial worker is obliged to take on two incompatible professional roles; Firstly, a patient-centered role and secondly, a loyal role towards the organization. As a consequence, these two incompatibilities tend to impact the self-regard of the psychosocial worker. In conclusion, psychosocial cancer care needs increased resources, and the benefit of closer professional collaboration between the medical cancer staff and the psychosocial cancer staff needs to be emphasized. Furthermore, awareness of the deficient conditions under which the psychosocial work is organized, need to be brought to the top management. This may allow the psychosocial cancer care to improve over time; and further facilitate psychosocial workers' abilities of administering equal and confident psychosocial cancercare. / Syftet med studien var att öka kunskapen om de hinder som existerar för den psykosociala yrkesutövningen inom cancervården. Genom en kunskapsöversikt där tio artiklar inkluderats, har det psykosociala yrkesutövandet inom cancervården i västvärlden undersökts utifrån cancerbehandlares perspektiv; vilka brister som syns i den psykosociala cancervården och vad som behöver förbättras för att kunna erbjuda den vård som lever upp till de behov som finns. Studiens resultat har tematiserats och analyserats med hjälp av Lipskys gräsrotsbyråkratiska teori. Resultaten visar att den psykosociala cancervården präglas av fyra brister; bristfälliga rutiner och avsaknad av struktur i den psykosociala vården, bristfällig psykosocial utbildning och kunskap hos medicinsk vårdpersonal, tids-, personal- och ekonomiska brister för det psykosociala arbetet samt brist på språk- och kulturanpassad psykosocial vård. Det framkommer att den psykosociala yrkesutövaren behöver inta två oförenliga roller i sitt arbete, dels att företräda patienten, dels att vara lojal gentemot sin organisation. Detta skapar otydlighet hos den psykosociala yrkesutövaren och kan även påverka dennes självbild. Utifrån studiens resultat, samt med hjälp av tidigare forskning, blir det tydligt att den psykosociala cancervården är i behov av ökade resurser, tätare samarbete och gemenskap med övrig medicinsk vårdpersonal. Dessutom behöver det psykosociala arbetet inom cancervården mobiliseras och organiseras för att lyfta yrkesområdets bristfälligheter, för att förändring ska kunna träda i kraft på en högre nivå. Detta för att kunna fortsätta leverera jämlik och trygg cancervård.

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<b><u>Introduction:</b></u> Some cancer survivors are known to have an elevated risk of morbidity and mortality from cardiovascular disease. An important cause of this elevated risk is recognised to be irradiation of normal tissues during radiotherapy received as part of cancer therapy. There are substantial difficulties in studying radiation-related cardiovascular disease (RRCD). The reasons for this include the complexities of measuring radiation normal tissue doses retrospectively and the prolonged latencies of many of the cardiovascular endpoints. A variety of complimentary research methodologies can help provide additional knowledge to guide the appropriate management of patients treated in the past and of new patients in the future. <b><u>Methods:</b></u> 1) A cohort study of mortality from circulatory disease in the nationwide British Childhood Cancer Survivor Study (BCCSS). 2) A case-control study of valvular heart disease (VHD) in Dutch Hodgkin lymphoma (HL) survivors, including retrospective radiation dosimetry to estimate the radiation dose to heart valves. 3) A dosimetric study of cardiovascular radiation doses in patients entered into the UK NCRI Lymphoma Study Group RAPID trial, including predictions of 15-year cardiac mortality using innovative methods. 4) A modelling study to predict mean whole heart dose (MWHD) from involved field radiotherapy (IFRT) for HL using anatomical measures. 5) A prospective study using cardiovascular magnetic resonance (CMR) imaging to characterise the heart in women receiving radiotherapy for breast cancer. <b><u>Results:</b></u> 1) The risks of all types of circulatory mortality are elevated in survivors of childhood cancer. The absolute excess risks continue to increase 40+ years following diagnosis. The risk of death from cardiomyopathy and heart failure increased substantially with the introduction of anthracycline chemotherapy. There is no evidence of a reduction in risk of circulatory mortality in more recent eras of diagnosis. 2) There is a strong relationship between estimated radiation dose to the affected heart valve and the risk of subsequent VHD (p<0.001). This effect was modelled to allow prediction of the risk of VHD. 3) A proportion of patients treated with IFRT received a substantial cardiac radiation dose (MWHD = 8.8 Gy, SD = 5.6) but, on average, the predicted 15-year cardiac mortality following treatment is low (absolute risk 0.2%, range 0.0 to 2.7%). 4) It is possible to estimate the mean whole heart dose from IFRT prior to detailed radiotherapy planning based on pre-treatment diagnostic imaging to an accuracy of 5-6% of the prescribed dose. 5) Although women received low cardiac doses (MWHD = 1.5 Gy, SD = 0.8) and have a low predicted risk of cardiac radiation-related morbidity and mortality, there is some evidence of subclinical effects on strain and strain rate imaging of the anterior portions of the left ventricle that receive the highest radiation dose. <b><u>Conclusions:</b></u> Using a variety of methods these studies have all succeeded in adding to knowledge about the nature, magnitude and timing of RRCD. This knowledge can be used to help the future management of cancer patients. In addition, each of the studies has natural and planned extensions and will continue to contribute further knowledge into the future.

Tumour tissue is characterised by fluctuating oxygen concentrations, decreased nutrient supply, and acidic pH. Angiogenic signalling pathways that drive a certain metabolic 'configuration' may give endothelial cells a selective advantage in the tumour environment. Previously it has been shown that glycolysis drives proliferation, migration and tip cell formation during sprouting of endothelial cells (De Bock, Georgiadou et al. 2013), and is increased by VEGFA. DLL4-NOTCH has been shown to limit angiogenesis and slow down proliferation of endothelial cells, and promote stalk cell formation during angiogenic sprouting, leading to sprout elongation. DLL4-NOTCH is implicated in tumour angiogenesis, and its overexpression is a potential mechanism of resistance to anti-VEGFA therapy (Li, Sainson et al. 2011). This thesis aimed at investigating the effect of the DLL4-NOTCH signalling pathway on endothelial metabolism and its implications in angiogenesis. Firstly, it was found that DLL4-NOTCH decreases the glycolytic rate and mitochondrial respiratory parameters in endothelial cells. When given exogenous fatty acids, DLL4-NOTCH activation caused increased fatty acid uptake, storage and oxidation. This shows that the induction of DLL4-NOTCH signalling results in increased fatty acid utilisation. Secondly, this research identified fatty acid oxidation as a target metabolism pathway for angiogenic therapy. More specifically, inhibition of fatty acid oxidation decreased proliferation of endothelial cells, decreased sprout elongation in the sprouting assay, and decreased sprouting from the axial vein in the zebrafish model. ATP production was not affected. Therefore, it was hypothesised that DLL4-NOTCH activation promotes and maintains the stalk cell phenotype through an increase of fatty acid oxidation, thereby promoting biomass production for endothelial cell proliferation and growth during angiogenic sprout elongation. Thirdly, a key fatty acid metabolism gene, fatty acid binding protein 4 (FABP4), was identified, that is positively regulated by NOTCH at its promoter region. FABP4 is a candidate for mediating increased fatty acid flux in endothelial cells in response to DLL4-NOTCH. This study shows that FABP4 is induced by VEGFA in a manner dependent on DLL4-NOTCH, and the insulin-responsive transcription factor FOXO1 was required for FABP4 expression in response to DLL4-NOTCH. FABP4 is pro-angiogenic and implicated in tumour angiogenesis in ovarian cancer omental metastasis. Taken together, this study shows for the first time that DLL4-NOTCH signalling increases FABP4 induction, contributing to a key pro-angiogenic pathway, and also fatty acid utilisation in endothelial cells, and thereby contributes to the formation of blood vessels.

FBXW7 encodes the substrate recognition component of an SCF E3 ubiquitin ligase complex. This complex regulates the degradation of multiple targets, such as Notch1, c-Jun, c-Myc and cyclin E, that function in critical developmental and cancer pathways. FBXW7 mutations are found in cancers of diverse tissue origins, with one of the highest mutation rates in the colorectrum. FBXW7 mutations are typically missense mutations that disrupt the substrate recognition domain at critical arginine propellor-tips. Mutations are often mono-allelic suggesting that FBXW7 is not a typical tumour supressor gene. Despite this, most of the evidence on FBXW7 function to date comes from null systems. Several Fbxw7 -null mouse models have been generated and suffer homozygous embryonic lethality due to disrupted vascular development. Conditional Fbxw7-null mice have been created but do not in general reflect the mutation spectrum found in human tumours. In order to analyse the functional effects of Fbxw7 propellor-tip missense mutations, mice carrying a commonly-occurring Fbxw7 R482Q mutation were generated. This propellor-tip mutation was knocked-in constitutively and whilst heterozygous mice developed normally in utero, they died perinatally due to defective lung development. Cleft palate and eyelid fusion defects were also observed with incomplete penetrance. Fbxw7 substrates were screened in embryonic lungs and significantly elevated protein levels of Klf5 and Tgif1 were observed. The Fbxw7 R482Q mutation was also conditionally knocked-in in the gut. In the heterozygous state, large adenomas in the small intestine were observed at a low multiplicity, in approximately 30% of mice at an age greater than 300 days. Upregulation of Wnt signalling and Ctnnb1 mutations have been identified in a selection of these tumours. Breeding the Fbxw7^R482Q allele onto Apc-mutant backgrounds led to accelerated morbidity, in which compound R482Q/Apc-mutant mice exhibited polyps of increased number and size. Elevated protein levels of Fbxw7 substrates Klf5 and Tgif1 were observed in adenoma and normal intestinal tissue from these mice. In vitro work using epitope-tagged murine wildtype and propellor-tip mutant Fbxw7 proteins showed that they were capable of dimerising, opening the prospect of investigating a dominant negative mechanism of action. To conclude, an Fbxw7 propellor-tip mutation studied in vivo resulted in both disrupted embryonic development and intestinal tumorigenesis and was distinct from Fbxw7 -null alleles.

Dissolution dynamic nuclear polarisation is an emerging clinical technique which enables the metabolism of hyperpolarised 13C-labelled molecules to be dynamically and non- invasively imaged in tissue. The first molecule to gain clinical approval is [1-13C]pyruvate, the conversion of which to [1-13C]lactate has been shown to detect early treatment re- sponse in cancers and correlate with tumour grade. As the technique has recently been translated into humans, accurate and reliable quantitative methods are required in order to detect, analyse and compare regions of altered metabolism in patients. Furthermore, there is a requirement to understand the biological processes which govern lactate pro- duction in tumours in order to draw reliable conclusions from this data. This work begins with a comprehensive analysis of the quantitative methods which have previously been applied to hyperpolarised 13C data and compares these to some novel approaches. The most appropriate kinetic model to apply to hyperpolarised data is determined and some simple, robust quantitative metrics are identified which are suitable for clinical use. A means of automatically segmenting 5D hyperpolarised imaging data using a fuzzy Markov random field approach is presented in order to reliably identify regions of abnormal metabolic activity. The utility of the algorithm is demonstrated on both in silico and animal data. To gain insight into the processes driving lactate metabolism, a mathematical model is developed which is capable of simulating tumour growth and treatment response under a range of metabolic and tissue conditions, focusing on the interaction between tumour and stroma. Finally, hyperpolarised 13C-pyruvate imaging data from the first human subjects to be imaged in Cambridge is analysed. The ability to detect and quantify lactate production in patients is demonstrated through application of the methods derived in earlier chapters. The mathematical approaches presented in this work have the potential to inform both the analysis and interpretation of clinical hyperpolarised 13C imaging data and to aid in the clinical translation of this technique.

Univerzita Karlova v Praze Přírodovědecká fakulta Studijní program: Filosofie a dějiny přírodních věd MUDr. Jan Hrudka Nádory v dějinném a kulturním kontextu v novověku Tumours in historical and social context in the modern period Disertační práce Školitel / Supervisor: Prof. RNDr. Stanislav Komárek, Dr. Praha, 2017 SUMMARY: The PhD thesis called Tumours in historical and social context in the modern period is an attempt to describe a change of medical thinking in modern period; science and medicine turns from antique humoral pathology, explaining all diseases as an imbalance of the four body humours, to pathological anatomy and experimental physiology. In the point of view of pathological anatomy, the viscera of diseased person are no more "screen" or "mirror" of the disease, but it becomes directly the "stage" or "theatre" of the acting disease. This shift in the thought may be labelled as movement from humoralism to localism or ontologism; the disease isn't just abnormal amount of some natural juice any more, but becomes new original entity. This change undergoes the understanding of tumours and cancerous disease as well. Instead of antique understanding tumours as precipitates of black bile, the cell theory occurs in the 19th century. This theory explains tumours as a mass of cells undergoing excessive...

Breast cancer type 1 susceptibility protein (BRCA1) has been established as an important tumour suppressor protein and its loss of function is associated with hereditary breast and ovarian cancer. An emerging body of work suggests that BRCA1 is involved in sporadic cases of breast and ovarian cancers and may also have a role in other cancers, indicating a more global role in tumourigenesis. BRCA1-mutated cancers can be early-onset and are characterised by being highly aggressive with a propensity to metastasize, thus from a clinical perspective there is a requirement to understand the molecular mechanisms in order to be able to tailor treatments and develop therapeutics. BRCA1 has numerous cellular functions, many ascribed to its role in maintenance of genome integrity, transcription and checkpoint control. More recently, a number of extra-nuclear roles have been established. An interesting novel function is the role of the E3 ubiquitin ligase activity on cell motility. Abrogation of the ubiquitin ligase activity of BRCA1 results in cells exhibiting a hypermotile, invasive phenotype which may help to account for the metastatic nature of BRCA1-mutated tumours. Our aim was to further elucidate BRCA1’s role in cell motility, starting with the identification of relevant candidate ubiquitin ligase substrates. To date, there has yet to be a systematic approach to identify BRCA1’s ubiquitin ligase substrates. Thus we undertook an unbiased proteomic approach to identify extra-nuclear candidates by comparing the profiles of ubiquitinated proteins in breast cancer epithelial cells expressing either functional BRCA1 or ubiquitin ligase-dead BRCA1. We identified 55 candidates which were differentially enriched between the two cell lines and through pathway analysis we determined a significant proportion were cytoskeletal and translation related proteins. Using an ubiquitin-remnant profiling approach, we also identified the site(s) of ubiquitination for many of the candidates. To assess the role of these candidates in cell motility initially we adopted an in silico approach. We used existing time-lapse movies from the online database (www.mitocheck.org) which systematically siRNA knocked down every single gene in the human genome. We developed a series of algorithms which track cell motility from these movies and used these to analyse 192,000 movies containing 3.5 billion cell steps. We have produced a complete database containing motility information after siRNA knockdown of every gene in the human genome, which has been annotated with gene ontologies, KEGG families, Gene Descriptions, SwissProt, Ensembl IDs and siRNA information. In addition to providing motility data of our candidates, we also carried out gene set enrichment analysis on the whole dataset to uncover structural or functional families that may be involved in up-regulating motility when knocked down by siRNA. This is the first report of a genome-wide motility database. Based on overlaps between the results from these two large-scale unbiased proteomic and in silico datasets, we selected 4 candidates, namely, ezrin, moesin, fermitin-2 and delta-catenin. Through monolayer wound healing, cell spreading and single cell motility assays, we determined that ezrin was a particularly relevant and informative candidate. The hypermotile phenotype observed in cells expressing ubiquitin ligase dead BRCA1 was rescued through siRNA knockdown of ezrin and thus we suggest that BRCA1 may regulate cell motility through effects on ezrin. This thesis has investigated candidate BRCA1’s role in cell motility, identified candidate substrates for the E3 ubiquitin ligase activity, established a genome-wide motility database and proposed a possible pathway through which BRCA1 may mediate cell motility and by extension metastasis.

The thesis " Women after Mastectomy in the context of Social Work " deals with the topic of diagnosis of breast cancer, treatments and their side effects, itself, however focuses mainly on the psychological and social consequences that come along with such a serious illness. It aims to outline the possibilities that women with this diagnosis can use , and ultimately points out the great potential of social work within the health care system. Powered by TCPDF (www.tcpdf.org)

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