Although the physiological consequences of Notch signaling in hematopoiesis have been extensively studied, the differential effects of individual notch cleavage products remain to be elucidated. Given that a disintegrin and metalloproteinase 10 (ADAM10) is a critical regulator of Notch and that its deletion is embryonically lethal, we generated transgenic mice that overexpress ADAM10 at early stages of lymphoid and myeloid development (A10Tg). ADAM10 transgene expression alters hematopoiesis post-hematopoietic Lineage-Sca-1+c-kit+ (LSK) subset differentiation but prior to lineage commitment of progenitor populations. This results in delayed T cell development, abrogated B2 cell development, and dramatic expansion of functionally active myeloid derived suppressor cells (MDSCs) in A10Tg mice. Given ADAM10’s role in Notch signaling, we hypothesized that the observed hematopoietic alterations may be a consequence of perturbed Notch signaling. In fact, blockade of ADAM10 (S2) rescues B cell development and reduces myeloid cells in A10Tg LSKs. Inhibition of γ-secretase (S3) in wild type (WT) LSKs results in enhanced myelopoiesis, mimicking the phenotype of A10Tg mice. Collectively, these findings indicate that the differential cleavage of Notch into S2 and S3 products regulated by ADAM10 is critical for hematopoietic cell-fate determination. Albeit arising in a tumor-free host, A10Tg MDSCs are functionally and phenotypically analogous to tumor-derived MDSCs. A10Tg MDSCs inhibit T cell activation in vitro, and inhibit adoptive immunotherapy (AIT) of metastatic melanoma in vivo, which can be reversed with MDSC depletion. Intriguingly, A10Tg mice are resistant to parasitic infection upon inoculation of Nippostrongylus brasiliensis. However, depletion of MDSCs abrogates this response, while adoptive transfer (AT) of MDSCs into WT mice increases their resistance. This polarized activity of MDSCs is heavily dependent upon interaction with mast cells (MCs). In fact, B16 melanoma cells metastasize more rapidly in WT mice infused with MDSCs when compared to MC-deficient mice (Kit Wsh/Wsh), with or without MDSC AT. Parallel to B16 progression, the ability of MDSCs to promote anti-Nb immunity is significantly diminished in MC-deficient (Kit Wsh/Wsh) mice even with MDSC AT. This augmentation of MDSC activity in the presence of MCs is further corroborated by in vitro co-culture assays that demonstrate a synergistic increase in cytokine production. Furthermore, MDSCs preferentially migrate to the liver in a MC-dependent manner. This interaction is mediated by MC-released histamine. In fact, MDSCs express histamine receptors (HR) and histamine induces MDSC survival, proliferation, and activation. We demonstrate that MDSC activity is abrogated with histamine blockade. Moreover, in humans, allergic patients present with an increase in MDSC population, and MDSCs purified from a stage I breast cancer patient exhibit increased survival in the presence of histamine. Taken together, our studies indicate that MCs and MC-released histamine are critical for the observed functional duality of MDSCs, ranging from immunosuppressive to immunosupportive, depending on the disease state.

A adoção é uma medida excepcional que visa à possibilidade de dar uma família às crianças e adolescentes privados da convivência familiar. Por isso, candidatos à adoção devem passar por um processo de preparação psicossocial e jurídica, orientado pelas equipes técnicas dos Juizados da Infância e Juventude. A falta de um critério norteador nas avaliações pode ser um trazer dificuldades para os profissionais que devem avaliar questões complexas como a adoção e a parentalidade. A partir disso, a presente dissertação teve como objetivo conhecer o funcionamento dos processos de habilitação para adoção no Rio Grande do Sul através de relatos dos psicólogos e assistentes sociais judiciários. Para isso, a dissertação foi composta por dois artigos. O primeiro apresentou os critérios levados em consideração, durante as entrevistas com postulantes à adoção, concluindo que, para os profissionais, a única motivação adequada é o desejo de ter filho e ser pai e mãe. O segundo mostrou as implicações de novos modelos e configurações familiares nos processos de habilitação para adoção, compreendendo as peculiaridades na avaliação de diferentes perfis de candidatos. Tendo em vista os dois estudos, foi possível analisar mais cuidadosamente os processos de habilitação para adoção no estado e pensar que ele poderia se configurar como um espaço de reflexão acerca do projeto adotivo e de parentalidade dos adotantes. Espera-se que este trabalho tenha contribuído para dar voz aos profissionais, voltar o olhar para os postulantes à adoção e aproximar uma área de estudo ainda incipiente no contexto acadêmico. / Adoption is an exceptional measure that aims at giving a family to children and teens that were deprived of in-family living, hence the candidates for adoption must go through a process psychological and judicial preparation guided by personnel from the Court of Infancy and Youth. The lack of a basal criterion in the evaluations brings a difficulty to the professionals involved that have to evaluate complex contexts surrounding adoption and parenting. The present study aimed at clarifying the functionalities and minutia of the process of habilitation for adoption in the state of Rio Grande do Sul through the accounts of psychologists and social workers allotted in the judiciary system. This dissertation is composed of two articles: the first one presented the criteria taken in consideration during the interview with the adopting candidates. It concludes that for the professionals involved in the screening process the main motivation should be the desire to have a child and to be a parent. The second article aimed at presenting the implications regarding the new configurations of family in the process of habilitation for adoption. It touches the details in the evaluation of different profiles of the candidates. Considering the two studies, it was possible to analyze more carefully the process of habilitation for adoption in the state and think the habilitation process can be itself as a ground to ponder upon adoptive and parental projects of the candidates. It is hoped that this study gave a voice to the professionals involved in the adoption process, emphasized the context of the candidates and bridged this still incipient field of research.

<p> </p><p>Becoming an adoptive parent is not always easy. There are positive and negative factors affecting the parent’s experience. The aim of this study is to examine being an adoptive parent to an internationally adopted child based on association, parenthood and ethnic belonging. Frame of interpretation consists of attachment and separations, parenthood and family and ethnic origin and belonging. In order to fulfil the purpose of the study qualitative interviews were made. The selection consisted of six adoptive families that were separately interviewed, one occasion each. The result indicated that some families did not experience any specific difficulties in their parenting whereas other families did. The experiences differed between those who had adopted an older child and those who had adopted a younger child. Association was considered a long and time consuming process. The parents did not consider it to be anything special about being and adoptive parent but they mentioned that the child at the homecoming displayed symptoms from having gone through an adoption. The reaction from the surroundings had not affected the families to any extent worth mentioning but they still expressed that the child’s appearance was important as they wished the child to be similar looking. The conclusion is therefore that it is something special about being an adoptive parent.</p><p> </p>

<p>This thesis deals with recognition and elimination of tumours by T lymphocytes and their use in adoptive immunotherapy.</p><p>The first tumour-draining lymph node; the sentinel node, is identified by peritumoural injection of a tracer. This is the hypothesised location for the activation of tumour-reactive lymphocytes. Accordingly, proliferation and IFN-γ production in response to autologous tumour extract was detected in sentinel nodes from patients with colon and urinary bladder cancer. Reactivity in metastatic nodes was generally lower or absent, but the non-responsiveness could be subdued in long-term cultures by addition of tumour antigen and IL-2. A novel padlock-probe based method was developed for measuring the T cell receptor Vβ repertoire. Common Vβ gene expansions were detected in tumour-infiltrating lymphocytes and sentinel nodes. Thus, tumour antigens are recognised in sentinel nodes by Th1 lymphocytes, resulting in a clonally expanded cell population that can be further propagated <i>ex vivo</i>.</p><p>Regulatory T cells (Tregs) may contribute to tumour-induced immunosuppression. Immunohistochemical stainings against the pan-T cell marker CD3 and Treg marker FOXP3 was performed on tumour tissue from 20 historical urinary bladder cancer patients. The ratio of FOXP3⁺ to CD3⁺ cells was lower in patients alive 7 years post-cystectomy, suggesting that Tregs in bladder cancer have prognostic implications.</p><p>Lymphocytes were isolated from sentinel nodes from sixteen patients with advanced or high-risk colon cancer. <i>In vitro</i> expansion with addition of autologous tumour extract and IL-2 mainly promoted the outgrowth of CD4⁺ Th1 lymphocytes, which were safely re-transfused to the patients. Four patients responded with complete tumour regression. Survival time in the Dukes’ D patients was significantly increased compared with conventionally treated controls (2.6 versus 0.8 years; p=0.048).</p><p>In conclusion, human solid tumours are recognised in sentinel nodes and <i>in vitro</i> expanded sentinel node-acquired CD4⁺ T lymphocytes seem useful in the treatment of patients with disseminated cancer.</p>

This thesis deals with recognition and elimination of tumours by T lymphocytes and their use in adoptive immunotherapy. The first tumour-draining lymph node; the sentinel node, is identified by peritumoural injection of a tracer. This is the hypothesised location for the activation of tumour-reactive lymphocytes. Accordingly, proliferation and IFN-γ production in response to autologous tumour extract was detected in sentinel nodes from patients with colon and urinary bladder cancer. Reactivity in metastatic nodes was generally lower or absent, but the non-responsiveness could be subdued in long-term cultures by addition of tumour antigen and IL-2. A novel padlock-probe based method was developed for measuring the T cell receptor Vβ repertoire. Common Vβ gene expansions were detected in tumour-infiltrating lymphocytes and sentinel nodes. Thus, tumour antigens are recognised in sentinel nodes by Th1 lymphocytes, resulting in a clonally expanded cell population that can be further propagated ex vivo. Regulatory T cells (Tregs) may contribute to tumour-induced immunosuppression. Immunohistochemical stainings against the pan-T cell marker CD3 and Treg marker FOXP3 was performed on tumour tissue from 20 historical urinary bladder cancer patients. The ratio of FOXP3+ to CD3+ cells was lower in patients alive 7 years post-cystectomy, suggesting that Tregs in bladder cancer have prognostic implications. Lymphocytes were isolated from sentinel nodes from sixteen patients with advanced or high-risk colon cancer. In vitro expansion with addition of autologous tumour extract and IL-2 mainly promoted the outgrowth of CD4+ Th1 lymphocytes, which were safely re-transfused to the patients. Four patients responded with complete tumour regression. Survival time in the Dukes’ D patients was significantly increased compared with conventionally treated controls (2.6 versus 0.8 years; p=0.048). In conclusion, human solid tumours are recognised in sentinel nodes and in vitro expanded sentinel node-acquired CD4+ T lymphocytes seem useful in the treatment of patients with disseminated cancer.

Becoming an adoptive parent is not always easy. There are positive and negative factors affecting the parent’s experience. The aim of this study is to examine being an adoptive parent to an internationally adopted child based on association, parenthood and ethnic belonging. Frame of interpretation consists of attachment and separations, parenthood and family and ethnic origin and belonging. In order to fulfil the purpose of the study qualitative interviews were made. The selection consisted of six adoptive families that were separately interviewed, one occasion each. The result indicated that some families did not experience any specific difficulties in their parenting whereas other families did. The experiences differed between those who had adopted an older child and those who had adopted a younger child. Association was considered a long and time consuming process. The parents did not consider it to be anything special about being and adoptive parent but they mentioned that the child at the homecoming displayed symptoms from having gone through an adoption. The reaction from the surroundings had not affected the families to any extent worth mentioning but they still expressed that the child’s appearance was important as they wished the child to be similar looking. The conclusion is therefore that it is something special about being an adoptive parent.

Sammanfattning Vi har gjort en kritisk diskursanalys av AC:s (Adoptionscentrum) medlemstidning under perioderna; 1975-1985, 1986-1996, 1997-2006. Frågeställningen lyder: Hur konstitueras diskursen om ”det goda adoptivföräldraskapet” genom AC:s medlemstidning? Vilka är möjlighetsvillkoren och vilka konsekvenser innebär diskursen? Vårt syfte har varit att förstå diskursen om ”det goda adoptivföräldraskapet”. Vi har utgått ifrån socialkonstruktioniskt, poststrukturalistiskt perspektiv och språkfilosofi. Vårt huvudsakliga resultat har visat sig vara att AC konstituerar diskurser som producerar och reproducerar ett antal normativa föreställningar om föräldraskap, familj och individer som bygger på socialt konstruerade föreställningar om vad som är en ”riktig” familj, bra föräldraegenskaper och barnets bästa. Diskursen ”det goda adoptivföräldraskapet” uppnås genom aktivt medlemskap i adoptionsorganisationen AC. Begreppet ”barnets bästa” har visat sig vara en flytande signifikant för att konstituera olika diskurser som alla handlar om att etablera eller upprätthålla AC som organisation. Genom barnets bästa har AC fått möjlighet att legitimera sina egna verksamhetsområden, styra över vem som är lämplig förälder, vem som får bilda familj och vika barn som är tillgängliga för adoption. Ytterligare resultat har visat på att AC under perioden fått ökad makt genom att förmedlingen av adoptivbarn har övergått till adoptivorganisationerna. Således har statens makt och inflytande fördelats över ytterligare en instans. / Abstract This essay is a critical discourse analysis on AC’s (Adoption Centre Organisation, Sweden) magazine for members during three periods; 1975-1985, 1986-1996, 1997-2006. Our main question is how discursive statements are made on “the good adoptive parenthood” in this magazine? What possible changeable meanings and truths are given by the discourses? Our aim is to understand the discourse “the good adoptive parenthood”. The theoretical framework consists of knowledge of social constructivism, post structural perspective and philosophy of language. Our main results are that AC constitutes discourses that produce and reproduce a number of assumptions about parenthood, family and individuals as normative and influenced by social constructed assumptions about what is; a “real” family, a good parenthood or “the child’s best interest”. The discourse of “the good adoptive parenthood” is gained through membership in the adoption organisation AC. The claim of “the child’s best interest” has in this essay being found as a fluent significant to constitute a variety of discourses, which all aim to establish and maintain the organisation. Through the principle of “the child’s best interest”, AC has found a way to legitimate their own fields, to decide who is a suitable parent, who shall form a family, and which child will be available for adoption. Further result shows that AC during the studied period has gained increased legal and governmental power in the field of adoption. As a result, the governmental power and influence in the adoption field has been divided through additional authorities.

The purpose of this study was to explore the potential benefits of a therapeutic horsemanship program for children adopted from foster care and their adoptive mothers. Standardized measures, open-ended interviews and surveys were administered to determine effects on external child behavior, child self-esteem and parenting stress. The Child Behavior Checklist was administered to measure behavioral challenges in the children in this sample. There were no statistically significant changes on any of the CBCL scales. Qualitative data from the mothers, Instructors and researcher observations show some affect on behavior. The Culture Free Self-Esteem Inventory-3 was administered to measure self-esteem of the nine children in the sample. The decrease on the Global Self-Esteem Quotient of the CFSEI-3 was statistically significant using. Of the nine children, only three of them scored in the clinical range at pre-test. Of these three, two moved into the normal range and the third improved her score to be very close to the normal range. Qualitative data from the mothers, Instructors and researcher observations support this finding. The Total Stress score of the Parenting Stress Index -- Short Form for the mothers in the sample did not show a statistically significant decrease. Six of the nine mothers' pre-test and post-test scores were in the clinical range and only three had decreased post-test scores. The Qualitative data obtained through interviews, surveys and observations did not support a direct impact of the program on stress levels but rather an impact on level of support. Many mothers reported that they liked spending time with the other mothers to share resources and discuss their children. The data collected in this study does not provide sufficient evidence to make any causal statements about therapeutic horsemanship programs and children adopted from foster care. It does, however, provide support for the need for future research. The findings from this study have implications for meeting the needs of a variety of children adopted from foster and their adoptive parents. / text

published_or_final_version / Social Work and Social Administration / Doctoral / Doctor of Philosophy

Ce projet d'étude qualitatif a pour but d'explorer, dans une perspective intersectionnelle, les défis rencontrés dans la parentalité homosexuelle masculine ainsi que les stratégies d'adaptation déployées afin de surmonter ces difficultés. Plus spécifiquement, ce mémoire vise 1) à identifier et à décrire les défis auxquels font face les hommes homosexuels qui ont adopté un ou des enfant(s) par la Banque-mixte ou en pays étrangers, et 2) à décrire les stratégies mises en œuvre afin de s'adapter à ces défis. Pour atteindre ces objectifs, une analyse qualitative a été effectuée à partir d'entrevues menées auprès de 10 hommes homosexuels québécois ayant adopté un ou des enfant(s) en Banque-mixte (7) ou en pays étrangers (3). L'analyse des témoignages permet de mettre en lumière une variété de défis rencontrés au cours des périodes de pré-adoption, d'adoption et de post-adoption, principalement chapeautés par l'hétérosexisme et l'hétéronormativité. À l'intersection du genre et de l'orientation sexuelle, les principaux défis rencontrés par les participants sont : le renoncement au projet parental suite à la prise de conscience de leur orientation sexuelle, la confrontation à des craintes de la part de l'entourage concernant la capacité parentale des hommes, les doutes de l'entourage concernant le sérieux du projet, la peur qu'on ne leur assigne aucun dossier d'enfant en raison de leur homosexualité, le sentiment de se mettre volontairement plus de pression sur les épaules dans l'exercice de leur paternité, l'intervention d'étrangers dans leur intimité familiale, la crainte que leurs enfants puissent être la cible de railleries parce qu'ils vivent dans une famille homoparentale et l'effritement de certaines amitiés homosexuelles. Qui plus est, il appert que le processus réflexif du mode d'accès à la parentalité et l'adoption en Banque-mixte et en pays étrangers comportent des enjeux et des défis distincts. À l'intersection du genre, de l'orientation sexuelle et de l'appartenance ethnique, les principaux défis rencontrés concernent principalement l'enjeu de la visibilité, la discrimination provenant d'individus partageant la même appartenance ethnique que celle de l'enfant et le racisme provenant des membres de la famille élargie. Les participants mettent également en place des stratégies diverses pour surmonter les défis liés à l'adoption d'un enfant et pour la gestion de la discrimination au quotidien. Des pistes d'intervention pour les professionnels œuvrant auprès des familles homoparentales masculines sont proposées en fin de mémoire. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : paternité, homosexualité, adoption, défis, stratégies d'adaptation, homoparentalité, intersectionnalité.