The effect of a progesterone receptor modulator on the endometrium and breast in premenopausal women

Background The levonorgestrel intrauterine system, LNG-IUS 52 mg, is a highly effective and costeffective contraceptive, entailing minimal patient effort. Irregular bleeding patterns are common during the first months of use and constitutes one of the main reasons for discontinuation. Up to date, no standard treatment approach has been proven to resolve this problem. Mifepristone is a synthetic steroid hormone, acting mainly as an inhibitor of the progesterone receptor (PR) thereby preventing the effect of progesterone. Administration of mifepristone has been proven beneficial in numerous fields in reproductive medicine and exerts various effects depending on the dosage and stage of the menstrual cycle at treatment. Administration of low daily doses of mifepristone results in anovulation and endometrial suppression with subsequent amenorrhea. Continuous treatment with PRMs cause endometrial alterations previously thought to be similar to unopposed estrogen exposure, given the PR antagonistic effects of PRMs. These alterations are today recognized as progesterone receptor modulator associated changes (PAEC). They are considered to be benign and dissolves with the cessation of treatment. The molecular alterations resulting in their development are still unknown. The mechanism of action of steroidal hormones on breast tissue remains largely unidentified. Epidemiological studies show a positive correlation between number of menstrual cycle exposure and hormone therapy to the risk of breast cancer. While this increased risk has been believed to be mainly caused by estrogen, a growing body of literature suggest progesterone and progestins to play a central role. PRMs can be used as a tool to study the effects of progesterone and holds potential to prevent breast epithelial cell proliferation. Aim The overall aim of this thesis is to explore the effects of the PRM mifepristone on the endometrium and on human breast tissue in premenopausal women. The specific objectives were to assess whether inducing amenorrhea with mifepristone, prior to placement of the LNG-IUS, could reduce the bleeding irregularities during the first months of use. Another objective was to evaluate the endometrial morphology after continuous treatment with mifepristone following insertion of the LNG-IUS, without prior endometrial shedding. Furthermore, we sought to explore how mifepristone alters the transcriptomic landscape in human beast in vivo and the epigenetic alterations observed in the breast tissue following PRM treatment. Materials, methods and results Study I was a prospective, randomized, placebo controlled, double-blind trial including healthy women with regular menstrual cycles opting for the LNG-IUS 52 mg for contraceptive purposes. Fifty-eight women were randomized whereof 29 to the mifepristone and 29 to the comparator group. Study participants received mifepristone, 50 mg every other day or a comparator. The pretreatment period with mifepristone was 2 months, followed by the LNG-IUS insertion. Women kept bleeding diaries as per instruction for the pretreatment period and until 6 months after placement of the device. After removing drop outs and exclusions, 19 women in the mifepristone and 19 in the comparator arm contributed to the final analysis. Bleeding diary data were analyzed as rates of bleeding and spotting days (B/S%) per treatment cycle. The results showed a significant reduction of B/S% during the pretreatment period in the mifepristone arm compared to placebo. Following insertion of the device, no statistical difference could be seen between the two groups. Women in Study II originated from Study I. Endometrial biopsies were retrieved at baseline, prior to the pretreatment period with mifepristone or the comparator. A second biopsy was retrieved at 3 months following LNG-IUS placement, with the IUS in situ. Nine paired biopsies from the mifepristone and 8 from the comparator group, contributed to the final analysis. The specimens were analyzed by an expert pathologist who was blinded to the treatment. All baseline biopsies where benign. The second biopsies were all benign and showed, as expected, changes due to progestin effect on the endometrium. There was no presence of PAEC. Participants in Study III originated from Study I. Core needle breast biopsies were collected at baseline and after 2 months treatment with mifepristone or the comparator. Paired biopsies from 16 women in the mifepristone group contributed to the analysis. The changes on mRNA expression level at baseline compared to after mifepristone treatment were screened using RNA sequencing. Functional annotation and pathway enrichment analysis of the differentially expressed genes (DEGs) revealed genes mainly involved in extracellular matrix (ECM) remodeling. In Study IV, patient cohorts and databases were used to generate and validate a breast tissue specific epigenetic index. That index was subsequently used to assess breast tissue samples from three clinical trials, including Study I. Based on the results from this specific epigenetic index, PRM treatment could exhibit favorable results in the mammary gland from healthy women as well as women with increased risk for developing breast cancer. Conclusion The applied mifepristone treatment regimen could not demonstrate any significant improvement in bleeding disturbances following placement of the LNG-IUS compared to placebo. Continuous treatment with mifepristone and subsequent LNG-IUS insertion without prior endometrial shedding, could represent a safe alternative regarding PAEC endometrial safety. Transcriptomic alterations in the breast after treatment with mifepristone revealed pathways mainly involved in ECM remodeling. Furthermore, epigenetic and genetic alterations in the breast following PRM treatment seem promising and suggestive of further investigations regarding the potential beneficial effects of these compounds in the prevention of breast cancer

Suche nach der Produktion einzelner Top-Quarks durch Flavor-ändernde neutrale Ströme mit dem CDF II Experiment

Verschiedene phaenomenologische Erweiterungen des Standard Modells sagen die Produktion von Einzel-Top-Quarks mittels Flavor-aendernden Neutralen Stroemen (FCNC) in fuehrender Ordnung vorher. Ein Beispiel fuer einen solchen Prozess ist u(c)+g->t, wobei ein Up-Quark, bzw. ein Charm-Quark, mit einem Gluon wechselwirkt und in ein Top-Quark uebergeht. Zur Suche danach werden Daten des CDF II Experiments mit der Signatur von einem Jet, fehlender Transversalenergie und einem Lepton verwendet

Narratives of incest

Incest is described by various models focusing on different factors ranging from pathology to descriptions of the ecosystem in which it takes place. This research presents a theoretical and practical description of father-daughter incest in a family where the father was not removed and includes narratives of all associated systems. Consistent with the postmodern, social constructionist and narrative theories, this study attempts to observe and describe the ensuing process of the incest narrative through the various systems within which it takes place. This process explores people's perceptions of incest, how these are assessed and interpreted, what kind of action they mapped out as a result and the possibility that the abusive narrative is being maintained. Implications for therapy with the incest family are discussed drawing on narrative principles. By utilising an emergent design the experiences and narratives of the family and related systems were permitted to emerge through the research process.PsychologyM.A. (Clinical Psycholog

Exploring stories of coping with childhood cancer in a support group for parents

This study examines through autoethnographic inquiry my research journey in the world of childhood cancer. The unfolding research experience eventually led to the focus of this investigation which is exploring stories of coping with childhood cancer in a support group for parents. Using the principles of ethnographic epistemology this study explores the stories of eight parents whose children were diagnosed with cancer and who decided to join the support group for parents called, TOUCH. An overview of the existing body of knowledge on childhood cancer and the family is presented as well as the value of a social support group in parenting a child with cancer. The need of a conceptual shift in order to understand the problem of parenting a child with cancer is propagated. The stories of eight parents within the setting of a social support group are presented. Through the principles of the qualitative method of ethnography the story of the child's cancer is described by means of emerging themes. The coping mechanisms used to cope in this world of uncertainty and ambiguity, follows. Finally the contribution of the support group is discussed in terms of my relationship with the group member, the group members' communication pattern and what was perceived to be helpful to the group member. The eight stories discussed all follow the same pattern. Four hypotheses emerged from the eight stories described and are presented in the final chapter. The strengths and limitations of the study are discussed as well as recommendations for future research.PsychologyD. Lit. et Phil. (Psychology

Du placenta aux figues sèches : mobilier funéraire et votif à Thasos

Deux figurines en terre cuite découvertes à Thasos, l’une votive, l’autre funéraire, nous conduisent, par leur ambiguïté,à se demander si les artisans ont donné une forme plastique au placenta humain alors même que les organes internes du corps ne sont presque jamais représentés. L’observation anatomique de l’« organe » comparée aux sources littéraires, médicales, épigraphiques et archéologiques offre des arguments valables pour appuyer l’hypothèse qu’il n’en a existé que des figurations indirectes, opérées à travers des métaphores imagées, selon le mode connu en anthropologie de l’image grecque. Les figurines en mettant le placenta humain sur la même échelle que les fruits, les céréales, les gâteaux et l’enfant, tous pensés comme relevant d’un processus de cuisson correspondant à la vie civilisée, nous permettent de saisir des éléments essentiels autour desquels la cité se structure et font de cet organe un symbole de la fécondité. Aussi, le placenta devient-il fruit offert à Déméter, gâteau associé à la naissance pour Artémis ou signe des rites de passage de la jeune fille destinée à procréer des enfants légitimes.Two terracotta figurines found in Thasos, one from a votive, the other from a funerary context, invite us, by their ambiguity, to question whether craftsmen did represent the human placenta in a time when internal organs are almost never depicted. The anatomical observation of this bodily part, compared with literary, medical and epigraphic sources, supports the idea that indirect, metaphorical representations did exist and conform to the anthropological logic of Greek imagery. The figurines place the placenta at the same level as fruits, cereals, cakes and the child, all seen as the result of a cooking process corresponding to civilized culture. Thus, the placenta becomes a fruit offered to Demeter, and a cake associated with childbirth, when offered to Artemis; it is also the sign of the rites of passage for girls who will give birth to legitimate offspring

Les figurines en terre cuite dans les sépultures d’enfants en Grèce ancienne : le cas des jeunes filles nues assises

This paper illustrates our methodological approach to archaeological funerary ensembles by focussing on the specific, but controversial, iconographical type, of a naked girl in sitting attitude, without a seat, that is still commonly called “doll” or “hierodoulos”. These representations are quite often found between the 4th and 1st centuries BC both in funerary contexts, where they form part of the grave goods accompanying mainly children and girls, and in votive contexts, such as the sanctuaries of Artemis, Aphrodite or the Nymphs. With regard to particular burials for which the context is known (Thasos, Abdera, Thessalonica), we aim to show that some old interpretations, still widely reproduced in recent literature, are not consistent with what we can deduce from the other categories of equipment and the identity of the deceased. Is it reasonable still to interpret these figurines as “hierodouloi” ? Or could they simply be young desirable women in the prime of life, practicing rituals that are suggested by the written and iconographical sources, consistent with the other gravefurnishings, and comparable with the votive deposits found in sanctuaries ? If the figurines are more particularly found in the graves of children, this colloquium provides an opportunity to reflect upon the method and purpose of the study of funerary offerings and their relationship with the dead child’s identity and history. The grave-goods do indeed form a language of signs, and convey a message that refers primarily to the identity of the deceased. Moreover, the specific occurrence of the same terracottas in both graves and places of worship evokes stages in the social and cultural life of the child

Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women

Background: Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. Methods: In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44). Results: Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. Conclusions: These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers

Search for the Higgs boson in events with missing transverse energy and b quark jets produced in proton-antiproton collisions at s**(1/2)=1.96 TeV

We search for the standard model Higgs boson produced in association with an electroweak vector boson in events with no identified charged leptons, large imbalance in transverse momentum, and two jets where at least one contains a secondary vertex consistent with the decay of b hadrons. We use ~1 fb-1 integrated luminosity of proton-antiproton collisions at s**(1/2)=1.96 TeV recorded by the CDF II experiment at the Tevatron. We find 268 (16) single (double) b-tagged candidate events, where 248 +/- 43 (14.4 +/- 2.7) are expected from standard model background processes. We place 95% confidence level upper limits on the Higgs boson production cross section for several Higgs boson masses ranging from 110 GeV/c2 to 140 GeV/c2. For a mass of 115 GeV/c2 the observed (expected) limit is 20.4 (14.2) times the standard model prediction.Comment: 8 pages, 2 figures, submitted to Phys. Rev. Let

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.