The existence of fetal microchimerism has been demonstrated many years ago. This phenomenon is associated with observation of two or more genetically different populations of cells present in one person. Fetal microchimerism originates naturally during pregnancy, by bidirectional transfer of the cells through placenta from fetus to mother (fetal microchimerism) and from mother to fetus (maternal microchimerism). In some cases fetal cells persisted in mother for decades after pregnancy. In my thesis I showed the presence of fetal microchimerism in tissues of endometrial cancer, breast cancer and ovarian cancer and in control, nonmalignant tissues. I worked with deep-frozen tissues, native tissues and cell cultures created from native tissues. I planed also the analysis of paraffin-embedded tissues; however this type of material showed to be unusable for fetal cells detection. On the contrary, native and deep-frozen tumor and control tissues are suitable for this type of research and fetal microchimerism was observed in part of samples. For detection and amplification of DNA extracted from tissues and cell cultures I used quantitative real-time PCR and SRY gene located on the Y chromosome as a marker of fetal cells. I detected the presence of male fetal cells. Fetal genome was found in both tumor and...

Des mutations acquises du gène TET2 ont été décrites dans les hémopathies malignes humaines. La fréquence de ces anomalies dans les hémopathies myéloïdes est de 10 à 20%, atteignant 50% dans les échantillons de leucémies myélo-monocytaires chroniques (LMMC). Les mutations observées sont inactivatrices, ce qui suggère que TET2 est un gène de type suppresseur de tumeur et que les mutations retrouvées conduisent à une perte de fonction de la protéine. Ce gène code pour une enzyme capable de modifier les cytosines méthylées. Il participerait ainsi au contrôle de la méthylation de l'ADN et donc à la régulation épigénétique de l’expression génique. Afin de mieux comprendre son rôle au cours de l’hématopoïèse, deux modèles murins d'inactivation du gène Tet2 ont été développés. Des expériences de greffe de cellules médullaires dans des souris syngéniques montrent que les cellules déficientes pour ce gène présentent un avantage compétitif par rapport aux cellules sauvages. L’analyse des souris invalidées pour ce gène montre une amplification des populations hématopoïétiques immatures, ainsi que des anomalies de la différenciation des lignages myéloïdes et également des lignages lymphoïdes. Une fraction des souris invalidées pour Tet2 âgées de plus de six mois développe des hémopathies malignes ressemblant à la LMMC humaine. Des anomalies équivalentes sont retrouvées dans les souris hémizygotes pour Tet2 et dans des souris portant un allèle hypomorphe du gène. L’ensemble de ces résultats montre qu’une dérégulation de l'activité de Tet2 conduit à des anomalies précoces de l'hématopoïèse, mais n'entraine pas directement la transformation des cellules progénitrices immatures. La latence du développement de ces tumeurs suggère la nécessité d'une coopération avec d'autres évènements oncogéniques, comme des anomalies d’autres acteurs épigénétiques / Acquired loss-of-function mutations of TET2 gene are frequently observed in patients with myeloid malignancies, including acute myeloblastic leukemia, myeloproliferative neoplasm, myelodysplastic syndrome, and chronic myelomonocytic leukemia (CMML). The Ten-Eleven-Translocation (TET) family proteins are 2-oxoglutarate/Fe(II)-dependent dioxygenases that catalyze the conversion of 5-methyl-cytosine into 5-hydroxymethyl-cytosine, which is proposed to constitute a first step toward cytosine demethylation. To study the function of Tet2 in murine hematopoiesis, we developed two mouse models in which the catalytic domain of the protein is disrupted. In both models, Tet2 deficiency leads to the progressive expansion of the immature hematopoietic compartment that includes stem cell and multipotent progenitors. In addition, both Tet2-deficient animals display abnormalities of erythroid, megakaryocytic, myelo-monocytic and lymphoid lineages, recapitulated in competitive transplantation assays. With age, Tet2-deficient mice develop bona fide myeloid tumors. All these properties were shown to be cell-autonomous by bone marrow cells transplantation and in vitro assays. Together these data suggest that TET2 activity is essential for normal homeostasis of the hematopoietic system. Its inactivation results in the development of hematologic disorders resembling human CMML myeloid disorders. TET2 deficiency endows the cells with a competitive advantage over wild type cells, induces hematopoietic differentiation abnormalities but is not responsible for full cellular transformation. The latency observed for CMML development in mouse models of Tet2 deficiency suggests a requirement for cooperating mutations, such other epigenetic regulator alterations.

Malignant tumours of the small intestine are rare. Age-standardised incidence in Europe is between 0.5-1.5 per 100 000. As the small intestine represents more than 90 % of the gastrointestinal mucosal surface, it is surprising that it gives rise to less than 2 % of gastrointestinal malignancies. The dominating histological subtypes are carcinoids and adenocarcinomas. We used three population-based registries in Sweden to study survival, second malignant tumours, causes of death, and Crohn’s disease as a risk factor for small intestinal adenocarcinoma and carcinoid. We evaluated tumour site, sex, age, and year of diagnosis as prognostic factors. For adenocarcinomas there was no difference in survival between duodenal and jejunal/ileal tumours. Women with jejunal/ileal adenocarcinomas showed higher probabilities of survival than men, while no such relation was found for duodenal tumours. Old age correlated with poor survival for duodenal tumours, and prognosis has improved in later years. For carcinoids, duodenal tumours had a more favourable prognosis than jejunal/ileal tumours. There was no difference in survival between sexes. Old age correlated with poor survival, and survival has improved in recent years. Female patients with adenocarcinoma had increased risk of acquiring cancer in the genital organs and breasts, and both sexes had increased risks of second tumours in the gastrointestinal tract and skin. Men with carcinoid tumours had increased risk of prostate cancer. Both sexes had increased risk of malignant melanoma and malignancies of endocrine organs. Patients with adenocarcinoma had increased risk of dying from malignant diseases other than the primary small intestinal cancer and from gastrointestinal disease. The cohort with carcinoid had higher than expected risk of dying from malignant disease, gastrointestinal disease, and cardiovascular disease. Patients with Crohn’s disease had increased risk of small intestinal adenocarcinoma and carcinoid, and the risk has increased for patients diagnosed in recent years.

Aim: The overall aim of this thesis was to describe and explore how sexuality, body image and HRQoL were affected in patients treated for hematologic malignancies, and their need for support. A further aim was to describe nurses’ conceptions of dialogues about sexuality. Methods: Ten nurses in cancer care (I) and twelve patients were interviewed (II). Data were analysed according to phenomenography (I-II). Data were also collected from patients (≥45 years) included consecutively: at baseline (n=32), one month (n=25; III-IV) and six months (n=20; IV) after treatment. Three instruments were used: SAQ-S, BIS and EORTC QLQ-C30. The data were analysed statistically. Main findings: The nurses (I) conceived that they should talk about sexuality with cancer patients, but usually did not due to their own attitudes, lack of knowledge about sexuality, communication skills and environmental conditions. The patients (II) experienced negative effects on sexual function and sexual relationship due to affected strength and sexual desire. The patients’ sexuality, body image and HRQoL were affected during (II-III) and one month after treatment (III-IV). Patients recovered with regard to these issues within six months, except for sexual relationship (IV). However, when the disease and side effects were experienced as severe, thoughts about and interest in sexuality were overshadowed, and the need or wish for support related to this issue was low (II). Sexuality and body image seemed to influence changes in HRQoL (IV). Conclusion: Patients above the age of 45 treated for hematologic malignancies with chemoimmunotherapy experienced problems related to sexuality, body image and HRQoL. However, as sexuality was found to be of low priority due to concerns for life when the disease and side effects were severe, support must be timely and individualized. Patient-centered care, with patients continuously meeting a nurse guided by the idea of holistic individual nursing care throughout the care trajectory, is suggested. / Sexuality is to a large extent seen as a private and sensitive topic by both patients and nurses in cancer care. The patients in this thesis were above the age of 45 and treated with chemo- or chemoimmunotherapy for hematologic malignancies. They experienced affected sexuality, body image and HRQoL during and after treatment. The importance of sexuality was low and sexuality seemed to be overshadowed when the disease and side effects were experienced as severe. Few patients described that information might have been helpful.  In order to avoid violating patients’ integrity, one challenge is to identify patients who ascribe importance to sexuality and who also want support regarding sexuality. One way is to organize care in a patient-centered way, with patients continuously meeting a nurse guided by the idea of holistic individual nursing care throughout the care trajectory. Furthermore, nurse educators’ need to acknowledge this area and the health care leaders should provide nurses opportunities to discuss attitudes and personal barriers to sensitive issues such as sexuality

Les mécanismes épigénétiques, tels que la méthylation et les modifications d'histones, sont impliqués dans le contrôle à grande échelle de l'expression du génôme et contribuent à la mise en place des profils d'expression des gènes spécifiques de tissus et de types cellulaires. Dans les cellules en cours ou en fin de différenciation, ces mécanismes sont aussi impliqués dans la mise en place et le maintien de la repression d'un grand nombre de gènes. La transformation oncogénique est presque toujours associée à des anomalies de la signalisation épigénétique cellulaire, dont certaines, comme les méthylations aberrantes de gènes suppresseurs de tumeur, sont considérées comme des événements oncogènes. Un aspect beaucoup moins étudié de ces dérégulations épigénétiques est l'activation aberrante de gènes tissu-spécifiques dans des cellules pré-cancéreuses et transformées. De nombreuses études rapportent l'activation « hors contexte » de gènes spécifiques du testicule dans plusieurs cancers somatiques. Ces gènes sont décrits sous le nom de gènes « cancer testis » ou C/T. Il a été suggéré que ces expressions illégitimes pourraient être de bons indicateurs des cancers, et fournir de nouvelles cibles pour une immunothérapie anticancéreuse. Au cours de cette thèse, nous avons développé une approche basée sur ce concept d'activation ectopique de gènes pour identifier les gènes exprimés de manière aberrante dans les lymphoblastes des patients atteints de leucémies lymphoblastiques aigues (LAL). Nous avons ensuite évalué leur intérêt pour une utilisation comme marqueurs pronostics et de prédiction de la réponse au traitement. Nous avons ainsi identifié une signature de huit gènes spécifiques de la lignée germinale / cellules souches embryonnaires, exprimés de manière aberrante dans les LAL pédiatriques et adultes : 4 gènes prédictifs de mauvais pronostic et 4 gènes associés à une issue favorable. Nous avons par la suite montré qu'une combinaison de l'expression de ces 8 gènes peut identifier les formes agressives de LAL chez les enfants ainsi que chez les adultes. Une étude prospective clinique a mis en évidence que notre système de détection des 8 gènes, basé sur un test RT- qPCR, pourrait aider à prédire la réponse précoce à un traitement (induction) dans un groupe de 31 patients adultes nouvellement recrutés, atteints de LAL. Enfin, en exploitant notre méthode de classification, nous avons découvert des traits biologiques communs entre les formes agressives de LAL chez les enfants et chez les adultes. Nos données montrent que les formes les plus agressives de LAL présentent les caractéristiques de cellules souches hématopoïétiques au repos. Cette information pourrait être utilisée pour adapter les approches thérapeutiques. Enfin, en plus de l'amélioration de la détection et du suivi des patients LAL, ce travail a un fort potentiel dans la définition de nouvelles stratégies thérapeutiques ainsi que d'ors et déjà dans les choix thérapeutiques les plus appropriés pour les patients porteurs des formes les plus agressives. / Epigenetic mechanisms such as methylation and histone modifications are involved in large-scale control of the expression of the genome and contribute to the development of specific gene expression profiles of tissues and cell types. In cells, during and after differentiation, these mechanisms are also involved in the establishment and maintenance of the repression of many genes. Oncogenic transformation is almost always associated with abnormalities of cellular epigenetic signalling, some of which, such as aberrant methylation of tumour suppressor genes, are considered as oncogenic events. One much less studied aspect epigenetic deregulations, is the aberrant activation of tissue-specific genes in pre-cancerous and transformed cells. Many studies have reported the “out of context” activation of specific testicular genes in several somatic cancers. These genes are described as the "cancer / testis" genes or C/T. It has been suggested that these illegitimate expressions could be good indicators of cancer and provide new targets for cancer immunotherapy. In this thesis, based on the concept of ectopic activation of genes, we have identified genes aberrantly expressed in lymphoblasts of patients with acute lymphoblastic leukemia (ALL). We have then assessed their potential for a use as markers for prognosis and prediction of treatment response. We have identified a signature of eight genes specific of germline/embryonic stem cells, aberrantly expressed in adult and paediatric ALL. The ectopic activation of four genes was predictive of poor prognosis and the expression of four other genes was associated with a favourable outcome. We have subsequently shown that the combination of the expression of these eight genes can identify aggressive forms of ALL in children and adults. A prospective clinical study showed that a test based on the detection of these 8 genes, by RT- qPCR could help predicting an early response to treatment (induction) in a group of 31 newly recruited ALL adult patients. Finally, using our classification method, we discovered common biological traits between aggressive forms of ALL in children and adults. Our data show that the most aggressive forms of ALL have characteristics of dormant hematopoietic stem cells. This information could be used to refine therapeutic approaches. Finally, in addition to improving the detection and monitoring of ALL patients, this work has great potentials in the definition of new therapeutic strategies as well as in the choice of the most appropriate therapeutic approaches for patients with aggressive forms of ALL.

In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We validated the signature as an independent marker in multivariate analysis and further reported that subset #2 cases were predominantly classified as i-CLL, although displaying a similar outcome as n-CLL. In paper III, we investigated the methylation status and expression level of miR26A1 in both CLL (n=70) and MCL (n=65) cohorts. High miR26A1 methylation was associated with IGHV-unmutated (U-CLL) and shorter overall survival (OS) in CLL, while it was uniformly hypermethylated in MCL. Furthermore, overexpression of miR26A1 resulted in significant downregulation of EZH2 that in turn led to increased apoptosis. In paper IV, we performed DNA methylation profiling in 176 CLL cases assigned to one of 8 major stereotyped subsets (#1-8) in relation to non-subset CLL (n=325) and different normal B-cell subpopulations. Principal component analysis of subset vs. non-subset CLL revealed that U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL, respectively, indicating common cellular origins. In contrast, subset #2 emerged as the first defined member of the i-CLL subgroup, which in turn alludes to a distinct cellular origin for subset #2 and i-CLL patients. Altogether, this thesis confirms the prognostic significance of RNA and epigenetic-based markers in CLL, provides insight into the mechanism of miRNA deregulation in lymphoid malignancies and further unravels the DNA methylation landscape in stereotyped subsets of CLL.

Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive. Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The e l,normous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with biologic activity. This review will describe the investigation and application of natural products derived from higher plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plant- derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia.

No description available.

The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies.

Bakgrund: Det är vanligt förekommande att patienter med hematologiskt maligna sjukdomar går från kurativ till palliativ vård. Hematologiska behandlingar beskrivs i litteraturen som högteknologiska, aggressiva och de mest förödande behandlingar människokroppen kan utsättas för. Tidigare studier visar att arbete inom cancervård, palliativ vård och vård i livets slutskede kan ha ogynnsam effekt på sjuksköterskors fysiska, psykiska och emotionella mående. Befintlig litteratur beskriver sjuksköterskors upplevelser av att vårda dessa patienter palliativt dock råder det avsaknad av beskrivning av sjuksköterskans upplevelse av att vårda patienter i övergången mellan kurativ vård och palliativ vård.   Motiv: Då det råder avsaknad av beskrivning av sjuksköterskors upplevelser av att vårda patienter i övergången mellan kurativ och palliativ vård ansåg författarna att det förelåg en kunskapsbrist gällande sjuksköterskors upplevelser samt hur dessa påverkar sjuksköterskan i den dagliga omvårdnaden av dessa patienter. Syfte: Syftet med studien var att beskriva och förstå sjuksköterskors upplevelser av att vårda patienter med hematologiskt maligna sjukdomar i övergången mellan kurativ och palliativ vård.Metod: Föreliggande studie utfördes som en kvalitativ semistrukturerad intervjustudie med induktiv ansats (n=8). Data analyserades enligt the Framework Analyzis. Resultat: Resultatet omfattar fyra teman som handlar om övergången mellan kurativ och palliativ vård: Konsekvenser av ovisshet i övergången, Kommunikation i övergången, Omvårdnad vid ovisshet i övergången och Sjuksköterskans upplevelser vid ovisshet i övergången. Konklusion: Övergången mellan kurativ och palliativ vård för patienter med hematologisk malignitet kan upplevas som otydlig och präglas av ovisshet, vilket leder till utmaningar i omvårdnaden av dessa patienter. Resultatet pekar på områden i behov av utveckling, till exempel behov av ett utökat teamarbete som i sin tur kan förbättra kommunikationen och öka personcentrering i vården av dessa patienter. / Background: It is common for patients with hematological malignancies to go from curative to palliative care. Hematological treatments are described in the literature as high-tech, aggressive and the most devastating treatments the human body can be subjected to. Previous studies show that work in cancer care, palliative care and end-of-life care can have an adverse effect on nurses' physical, mental and emotional well-being. Existing literature describes nurses' experiences of caring for these patients palliatively, however, there is a lack of description of the nurses' experience of caring for patients in the transition between curative care and palliative care. Motive: As there is a lack of description of the nurses' experience of caring for patients in the transition between curative and palliative care, the authors believed that there was a lack of knowledge regarding nurses' experiences and how these affect the nurse in the daily care of these patients. Aim: The aim of the study was to describe and understand nurses' experiences of caring for patients with hematological malignancies in the transition between curative and palliative care. Methods: The present study was conducted as a qualitative semi-structured interview study with an inductive approach (n=8). Data were analyzed with Framework Analysis. Result: The result includes four themes relating to the transition between curative and palliative care: Consequences of uncertainty in the transition, Communication in the transition, Nursing in the event of uncertainty in the transition and The nurses' experiences in the event of uncertainty in the transition. Conclusion: The transition between curative and palliative care for patients with hematological malignancies can be experienced as unclear and characterized by uncertainty, which leads to challenges in the care of these patients. The results point to areas in need of development, for example the need for increased teamwork which in turn can improve communication and increase person-centered care in the care of these patients.