Background: A positive BRCA1/2 carrier status impacts an individual on various levels with implications to an entire family due to shared family genes. A gap exists in the research literature in the area of parental disclosure and non-disclosure of genetic test results to younger offspring. Additional studies in the area of parental disclosure and non-disclosure will help clinicians to better support parents and children during this process. Purpose: The purpose of this qualitative hermeneutic phenomenological research study was to attain an understanding of the lived experience of parents’ perceptions regarding the disclosure and non-disclosure of a positive BRCA1/2 test result to minors. Results: The essence of the lived experience of the 15 study participants was a parental desire for healthcare professionals to take the BRCA1/2 conversation a step further which was uncovered in the seven research themes. Discussion: For the study participants interviewed, stories reflected an identified need for axillary support that specifically pertained to the disclosure and non-disclosure decision-making process. Findings suggest ways in which parental support may be coordinated though intra and interdisciplinary team approaches to patient care. Implications: The findings from this study support the need for mixed methods studies of parental disclosure and non-disclosure of BRCA1/2 test results to minors. Specifically, studies assessing positive BRCA1/2 males and individuals from our gay community, members from our lower socioeconomic and diverse ethnic community, and fathers and children’s perceptions regarding the disclosure of parental BRCA1/2 test results to minors are warranted.

No description available.

The advent of cDNA microarray technology has allowed the study of diseases such as epithelial ovarian cancer (EOC) to occur at an unprecedented level of molecular resolution. (For complete abstract open document)

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 4 uppsatser.

Ovarian cancer (OvCa) is the most fatal gynecological malignancy, with over 21,290 new cases diagnosed in 2015. The 5 year survival rate for patients diagnosed at Stage IV is 17% in the United States. It has been reported that estrogen (E2) can promote metastasis of ovarian tumor cells through its nuclear receptor (ER). E2 is a potent mitogen and can stimulate the growth and invasion of ovarian cancer cells. We have previously shown that flaxseed diet decreases the severity and incidence of OvCa in hens, the only animal model that develops OvCa spontaneously and the disease is pathologically and histologically similar to the human disease.. While it is well established that the n-3 polyunsaturated fatty acids from flaxseed are anti-inflammatory the phytoestrogenic properties of its lignan, secoisolaricirescinol diglucoside (SDG) have not been fully explored. SDG metabolites, enterolactone (ED) and enterodiol (EL) can decrease ER signaling by competing for binding sites with E2, potentially decreasing expression of E2 target genes involved in proliferation and survival. Our goal was to analyze the effect of flaxseed diet on E2 signaling and metabolism in the normal and cancerous ovarian tissues. We hypothesized that due to the phytoestrogenic properties of the flax lignan, flaxseed diet can affect the downstream signaling of ER there by altering the expression of its target genes. In the 3 year old pre-neoplastic hen ovaries, 15% flaxseed supplemented diet was most effective in decreasing the expression of ER and its target genes like IGFBP4, IGFBP5, IRS1 that are a part of the IGF signaling pathway and are also implicated in a significant number of malignancies. Whole flaxseed diet also decreased the expression of the anti-apoptotic protein, BCL2L1 possibly by reducing the activation of the NFkB pathway. Ovarian tumors from 4 year old hens appeared to over-express estrogen receptor along the glandular area of the tumor but not the stroma. In the 3 year old pre-neoplastic hen ovaries, whole flaxseed and its components, defatted flax meal and flax oil decreased AKT2 mRNA expression but did not affect its activation. Another major regulator of intracellular signaling, ERK 1/2 MAPK appeared to be upregulated in tumors from flaxseed fed hens. Whole flaxseed diet was also significant in altering the metabolism of E2. This was suggested by the increased 2-hydroxyestrone/16-hydroxyestrone (2OHE/16OHE) ratio (a marker for reduced risk of cancer), in the serum from normal hens that were fed 15% flaxseed. It was also demonstrated that whole flaxseed and its components led to a significant decrease in CYP1B1 expression, an enzyme frequently upregulated in cancers, in the hen ovarian tumor tissues. Levels of the pro-apoptotic and anti-proliferative metabolite, 2-methoxyestradiol were significantly increased with whole flaxseed diet in the serum from 3 year old (pre-neoplastic hens) as well as 4 year old hens (cancerous and normal hens). These results demonstrated that whole flaxseed had a more significant effect in decreasing the expression of the cancer implicated end-points and increasing the levels of protective metabolites in comparison to either of its components, individually. Mechanistic studies with the in vitro model using the BG1FR ovarian cancer cells indicated that that 2-methoxyestradiol could induced apoptosis with a parallel increase in p38 activation. Since we observe a similar correlation between 2-methoxyestradiol and p38 in vivo, we believe that flaxseed diet maintains an anti-proliferative, anti-inflammatory and pro-apoptotic ovarian microenvironment by increasing 2-methoxyestradiol levels.

目的：收集及整理近5 年有失治疗卵巢早衰的中医和中西医结合文献，对该病的病因病机、治疗原则和方法，以及中医处方用药及临床疗效进行统计分析、归纳及总结，探寻卵巢早衷的证治方法和用药规律’为今后的中医药治疗提供系统化思路和文献学基础。方法：对收集到的符合标准的85 篇文献进行病因病机、证治方药和臨床疗效的归纳，并用Excel 软件建立数据库并进行数据统计分析。结果：通过对85 篇文献分析’卵巢早衰常见病因病机共有11 大类：肾精亏虚、肾虚肝郁、括子血阻滞、肾阳虚、肾阴虚、脾肾两虚、肝肾阴虚、气血不足、心肾不交、痰湿阻滞、以及其他。肾精亏虚所占比例最大，为29.26% 。将与“肾虚”相关的所有病机一起合计，所占比例为75.58% 。治疗药物出现总体频次为1292 味次，其中居第一位为补益药，共849 味矢，占65.71% ；居第二、第二位的分别为活血桔痕药， 165 味女，占12.77% ；清热药， 66 味矢，占5.11% 。高频药物：熟地、当归、莞丝子、山药、山英肉、构丰己子。结论：肾虚是卵巢早衰发病的根本病因病机，肝郁气滞和膝阻；中任是发病的主要环节。提出临床治疗该病的基本思路与方法为： (1 ）补肾为玉，佐以疏肝养肝、健脾养心是治本之法；（ 2 ）标本兼治，活血化插手是卵巢早衰主要的治标之法；（ 3)滋阴柔肝、清热凉血也是卵巢早衰常用的治疗方法之一；（ 4 ）中药周期疗法和辨证论治相结合；（ 5 ）身心同治，配合心理疏导。關键词：卵巢早衰；中医药治疗卵巢早衰；现代临床文献研究；病因病机；证治方药

Ovarian carcinoma is considered to be the most deadly of the gynaecological malignancies which in its earliest stages is usually asymptomatic. The unsatisfactory survival rates of patients on conventional chemotherapy regimens, necessitates vehicles capable of carrying cytotoxic agents directly to the malignant cells. This mode of targeted delivery allows for efficient tumour cell kill whilst sparing surrounding normal tissue and substantially reducing side-effects. This project examined the possible therapeutic role of a targetable sustained drug delivery system, albumin immunomicrospheres containing the chemotherapeutic agents, cisplatin and 5-fluorouracil, for the treatment of ovarian adenocarcinoma. A rodent cell line, as a model, has proved to be similar to its human counterpart and also has shown to be transplantable from one animal to another. Such a model could therefore be useful for performing experiments relating to drug delivery targetability and therapeutic trials, as well as survival studies, in cases of ovarian adenocarcinoma. In particular, this project examines the efficacy of the immunospecific microspheres containing the drugs in a highly concentrated form, administered intraperitoneally and targeted to an ovarian adenocarcinoma, in an attempt to enhance tumour cell kill whilst largely sparing surrounding normal tissue. It is widely recognized that the effectiveness of most chemotherapeutic drugs would be enhanced if they were to act selectively where they are needed. In order to achieve a therapeutically relevant dose in tumour cells, the amount of drug required usually proves also to be highly toxic to normal tissues. It was postulated that, to overcome the above, it may be feasible to develop a sustained immunospecific drug delivery system to optimize the action of cisplatin and 5-fluorouracil at the target site. With the attainment of the above, it was further postulated that higher doses of drugs could be delivered to the target area effecting higher tumour cell kill, that less normal tissue damage should occur and that toxic side effects of the drugs should be reduced. The rationale for selecting combination therapy of cisplatin and 5-fluorouracil is that, although it has been inferred that DNA intrastrand and interstrand cross-links produced by the cisplatin often repair, this repair can be blocked by 5-fluorouracil by inhibition of thymidylate synthetase, thus preventing DNA strand repair. Albumin immunomicrospheres are relatively innocuous in terms of toxicity, non-antigenic and are capable of accommodating chemotherapeutic agents in a non-specific fashion. We showed that they were capable of a 0. 94% entrapment of 5-fluorouracil and 1.23% cisplatin. Delivery of these drugs at a target site, and at these concentrations, should effect extensive cell kill. As the microspheres are chemically stable and can be manipulated to offload the entrapped drugs satisfactorily, in vitro drug release profiles were performed employing immunospecific microspheres directed towards its target cells. Slow degradation of the drug- containing albumin immunomicrospheres showed that 0.283 μg cisplatin/ml plasma and 0. 799 μg 5-fluorouracil/ml plasma could be made available at the target site over a 14-day period. These concentrations could be maintained over at least another 14 days and effect tumour cell kill satisfactorily. In order to assess the tumour cell kill, we performed clonogenic assays, cell survival growth curves, MTT cytotoxicity assays and assessed the induction of micronuclei in the tumour cells. The synergism between 5-fluorouracil and cisplatin showed a modulation of cisplatin cytotoxicity and total tumour cell kill was achieved at concentrations of 0.5 μg/ml 5-fluorouracil and 0.1 μg/ml cisplat in at the target site. The above-mentioned evidence of effective targeting of the drugs was then investigated in female Wistar rats with ovarian adenocarcinoma to assess comparative survival times when treated with free drugs or immunospecific albumin microspheres containing the drugs. Animals given a free drug dose of 5 mg/kg cisplatin and 20mg/kg 5-fluorouracil, followed by a repeat dose at the same concentrations 7 days later showed that only 14% of the animals survived a 90-day trial period. Animals given an intraperitoneal bolus dose of immunomicrospheres at a dose of 1 O mg/kg cisplatin and 40 mg/kg 5-fluorouracil showed that 60% of the animals survived the 90-day trial period. This data indicated to us that the survival probability of animals treated with drug-containing immunomicrospheres was substantially superior to other protocols employed in this study.

Introdução: A criopreservação de fragmentos de tecido ovariano previamente ao início da terapia oncológica e posterior reimplante do tecido ovariano tem sido sugerido como promissora alternativa para preservação de fertilidade. Neste sentido, um novo sistema de vitrificação denominado Ovarian Tissue Cryosystem (OTC), vem sendo desenvolvido visando aperfeiçoar a conservação do tecido congelado. Objetivo: Avaliar o impacto da criopreservação sobre a viabilidade do tecido ovariano murino vitrificado por três diferentes protocolos, dentre eles o sistema OTC. E avaliar o impacto do reimplante heterotópico do tecido ovariano murino fresco e descongelado pelos mesmos protocolos, sobre a sua viabilidade. Metodologia: Este é um estudo experimental onde foram utilizados tecido ovariano de camundongos C57BL/6. Três protocolos de vitrificação foram testados simultaneamente: protocolo murino (PrM); protocolo humano (PrH); protocolo OTC (PrOTC) em comparação ao grupo frescos (GF). As amostras foram analisadas imediatamente após o descongelamento (Etapa 1) ou após 15 ou 30 dias de reimplante retroauricular (Etapa 2). Para análise da viabilidade utilizou-se imunohistoquímica para proliferação celular (Ki-67), dano celular (NF-kB) e dano oxidativo (4-HNE e Nitrotirosina). Os resultados foram obtidos utilizando-se o teste Q-quadrado para verificar a distribuição entre os grupos e a imunomarcação (% de folículos marcados), sendo que o nível de significância adotado foi p<0,05. Resultados: Etapa 1: Os grupos PrOTC e PrM apresentaram melhor desempenho em relação à proliferação celular. Entretanto, estes mesmos protocolos apresentaram graus variados de dano oxidativo quando analisados pela imunomarcação de nitrotirosina, aonde o PrOTC teve maior marcação do que o GF, portanto maior dano, e o PrM teve maior marcação em relação ao HNE em comparação com os demais protocolos. Não houve nenhuma diferença na marcação do NF-kB entre os grupos descongelados. Etapa 2: O reimplante em si não pareceu comprometer significativamente o tecido, uma vez que as amostras GF e GF reimplantado com 15 e 30 dias tiveram desempenho semelhante em relação à todos os marcadores, com exceção do GF 30 dias que mostrou algum grau de dano oxidativo pela nitrotirosina (p<0,05). E ao se avaliar a somatória de efeitos entre congelamento e reimplante entre os diferentes protocolos apenas o PrH evidenciou dano tecidual imediatamente após o descongelamento e dano progressivo após o reimplante. Conclusão: Os PrM e PrOTC foram semelhantes ao GF na conservação da amostra durante o processo de criopreservação, sendo que o PrOTC causou algum grau de dano oxidativo. O reimplante retroauricular do tecido não impactou sobre a sua viabilidade do mesmo nem no GF e nem nos PrM e PrOTC. O PrH mostrou-se inadequado para a conservação de tecido ovariano murino. / Introduction: The Cryopreservation of fragments of ovarian tissue prior to initiation of oncotherapy and subsequent reimplantation of ovarian tissue has been suggested as promising alternative for fertility preservation. In this sense, a new system of vitrification called Ovarian Tissue Cryosystem (OTC), has been developed in order to improve the frozen ovarian tissue conservation. Objective: To compare the viability of murine ovarian tissue vitrified by three different vitrification protocols and to verify the efficiency of the Ovarian Tissue Cryosystem (OTC). Methods: This is an experimental study using ovarian tissue of C57BL/6 mice. Three vitrification protocols were tested simultaneously: Murine protocol (PrM); Human Protocol (PrH) and Protocol OTC (PrOTC); in comparison to Fresh Tissue (GF). Samples were analyzed immediately after thawing (Step 1) or after 15 or 30 days of retroauricular reimplantation (Step 2). For viability analysis immunohistochemistry for cell proliferation (Ki-67), cell damage (NF-kB) and oxidative damage (4-HNE and Nitrotyrosine) was used. The results were obtained using the Q-square test to analyze immunostaining counted as % of labeled follicles and the level of significance was set at p <0.05. Results: Step 1: The PrOTC and PrM presented the best performance in relation to cell proliferation. However, these same protocols presented varying degrees of oxidative damage when analyzed by the nitrotyrosine immunolabeling, where PrOTC had higher marking than GF, thus greater damage, and PrM had a greater marking in relation to HNE compared to the other protocols. There was no difference in the labeling of NF-kB between the thawed groups. Step 2: The reimplantation procedure did not appear to significantly impair the ovarian tissue quality once day 15 and 30 after fresh tissue engrafment of was similar for all markers except for nitrotyrosine after 30 days (p<0,05). And when assessing the sum of effects of freezing and reimplantation among the 3 different protocols only PrH showed tissue damage immediately after thawing and progressive damage after reimplantation. Conclusion: The PrM and PrOTC were similar to the GF in the preservation of the sample during the cryopreservation process, and PrOTC caused some degree of oxidative damage. Retroauricular reimplantation of the tissue did not impact on its viability in either the GF or PrM and PrOTC. PrH was found to be unsuitable for the cryopreservation of murine ovarian tissue.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser.