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1
Anderson, Philip D. "Genetic control of testicular germ cell tumor susceptibility in mice." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1247182449.
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Gels, Maria Elisabeth. "Testicular germ cell tumors developments in surgery and follow-up /." [Groningen] : [Groningen] : Rijksuniversiteit Groningen ; [University Library Groningen] [Host], 1997. http://irs.ub.rug.nl/ppn/15817464X.
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Mitchell, Roderick T. "Germ cell development in the human and marmoset fetal testis and the origins of testicular germ cell tumours." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4818.
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Normal germ cell development in the human testis is crucial for subsequent fertility and reproductive health. Disruption of testis development in fetal life can result in deleterious health consequences such as testicular dysgenesis syndrome (TDS), which includes disorders, such as cryptorchidism, hypospadias, infertility and testicular germ cell tumours (TGCT). A rat model of TDS in which rats are exposed to phthalates in utero has been validated, but does result in the development of TGCT. In humans, TGCTs result from transformation of pre-neoplastic carcinoma in-situ (CIS) cells and these CIS cells are believed to arise from human fetal germ cells during their transition from gonocyte to spermatogonia, based on their morphology and protein expression profile. It has been proposed asynchronous differentiation of germ cells in the human fetal testis may predispose fetal germ cells to become CIS cells. Studying the development of these tumours in humans is difficult because of their fetal origins and prolonged duration from initiation of impaired development to invasive disease. For this reason the use of relevant animal models that can mimic normal and abnormal germ cell development may provide new insight into how TGCT develop. The Common Marmoset monkey, a New World primate exhibits many similarities to the human in terms of reproductive biology and could represent such a model. This thesis aimed to further characterise the origins of CIS cells in the human testis by investigating the protein expression profile of CIS cells in patients with TGCT and comparing them to established markers of human fetal germ cell types using immunohistochemistry and immunofluorescence. Quantification of the various subpopulations of CIS and proliferation within these populations was performed. The thesis also investigated the Common Marmoset monkey as a potential model of normal testis and germ cell development by comparing the differentiation and proliferation profile of germ cells with those of the human during fetal and early postnatal life. During the present studies methods were successfully developed that enabled us to use testicular xenografts to recapitulate normal development of immature testes from marmoset and human. This involved grafting pieces of testis tissue subcutaneously under the dorsal skin of immunodeficient mice and retrieving them several weeks later to investigate their development during the grafting period. Xenografts using tissue from fetal, neonatal and juvenile marmosets were performed in addition to testes from first and second trimester human fetuses. Finally the present studies aimed to use the marmoset and the xenografting approach as systems in which to examine the effects of gonadotrophin suppression and phthalate treatment on germ cell differentiation and proliferation, with particular attention to the potential for development of CIS and TGCT. Heterogeneous phenotypes of CIS cells were identified, mostly consistent with those seen in the normal human fetal testis, however some of these CIS cells did not exhibit the same phenotype as germ cells identified in normal fetal testes. In addition it was shown that some of the proteins considered to be ‘classical’ markers of CIS cells, such as the pluripotent transcription factor OCT4, were not expressed in a proportion of the CIS cells. The proliferation index of CIS cells is also significantly higher in those subpopulations with the most ‘undifferentiated’ phenotype (i.e. OCT4+/VASA-). The present studies have generated novel data showing that the marmoset is a good model of fetal and neonatal germ cell development, with similarities to the human in terms of an asynchronous and prolonged period of differentiation and proliferation of germ cells from gonocyte to spermatogonia. This feature is also common to the human, but not a characteristic of the rodent. Fetal, neonatal and pre-pubertal germ cell development can be re-capitulated by xenografting tissue from marmoset and human testes into nude mouse hosts. Human fetal testis grafts produced testosterone and were responsive to hCG stimulation. First trimester human testis xenografts that have not developed fully formed seminiferous cords prior to grafting can complete the process of cord formation whilst grafted in host mice. In addition, germ cells in fetal human and marmoset xenografts can differentiate and proliferate in a similar manner to that seen in the intact non-grafted testis. In the intact neonatal marmoset, suppression of gonadotrophins resulted in a 30% decrease in proliferation, however differentiation of gonocytes is not affected. In-utero treatment of neonatal marmosets with mono-n-butyl phthalate was associated with unusual ‘gonocyte’ clusters, however, di-n-butyl phthalate treatment of mice carrying fetal marmoset xenografts resulted in no visible effects on germ cell differentiation or proliferation and did not result in the development of CIS or TGCT. In conclusion, this thesis has shown that there are many subpopulations of CIS cells of which many have not been previously described. These subpopulations have different characteristics, such as variable proliferation rates and this may indicate the potential for progression or invasiveness. These subpopulations have similar protein expression phenotypes to normal human fetal germ cells although the present studies have identified some CIS cells with phenotypes that are not found in the normal human testis. This thesis has demonstrated that the marmoset is a comparable model to the human in terms of asynchronous fetal germ cell development, which may predispose this species to the development of CIS/TGCT. In addition to the use of intact marmosets, these studies have also demonstrated for the first time that testis xenografting provides a comparable system for testis cord formation, germ cell differentiation and proliferation in fetal/postnatal marmosets and fetal human testis. In addition the marmoset and xenografting models have indicated that phthalates may have minor effects on testis development in the human and marmoset but do not result in CIS or TGCT. These model systems are suitable for further investigation of normal and disrupted testis development.
4
Nastaly, Paulina [Verfasser], and Klaus [Akademischer Betreuer] Pantel. "Detection and characterization of circulating tumor cells in patients with testicular germ cell tumors and prostate cancer / Paulina Nastaly. Betreuer: Klaus Pantel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1059237822/34.
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5
Fung, Ka-lai, and 馮家禮. "Significance of MAD2 in mitotic checkpoint control and cisplatin sensitivity of testicular germ cell tumour cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39357727.
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Fung, Ka-lai. "Significance of MAD2 in mitotic checkpoint control and cisplatin sensitivity of testicular germ cell tumour cells." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38588912.
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Quevedo, Francisco Carlos [UNESP]. "Tumores testiculares germinativos não-seminomas: imunoexpressão protéica de EGFR, Her2 E c-Kit." Universidade Estadual Paulista (UNESP), 2017. http://hdl.handle.net/11449/151631.
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As neoplasias testiculares constituem aproximadamente 1% dos cânceres masculinos. Dentre eles, os tumores que têm origem nas células germinativas (TTCG) são os mais frequentes. Por sua natureza, esses tumores têm padrão morfológico variado, sendo distribuídos em dois subgrupos: os seminomas e os não-seminomas. Esses últimos, por sua vez, são classificados em carcinomas embrionários, tumores do seio endodérmico, coriocarcinomas, teratomas e tumores mistos de células germinativas. Há consenso na literatura de que a invasão vascular verificada histologicamente no tumor primário é o melhor indicador preditivo de progressão da doença e recidiva. Estudos recentes demonstram o papel dos fatores de crescimento e seus receptores para avaliação prognóstica dos TTCG, no que o uso da imuno-histoquímica é fundamental. O presente estudo procurou avaliar pela técnica imuno-histoquímica à ocorrência da expressão do receptor do fator de crescimento epidérmico (EGFR), do Her2 e do c-Kit em uma série de TTCG não-seminomas primários de testículo. Além disso, explorou a possível relação entre a expressão desses marcadores com a evolução dos pacientes após terapêutica convencional. A série foi constituída de amostras parafinadas existentes no Laboratório de Anatomia Patológica e Citologia do Hospital Amaral Carvalho de Jaú, totalizando 103 pacientes que receberam o diagnóstico de tumor testicular de células germinativas não-seminomas (TTCGNS) no período 1996-2010. Dentre os 103 casos, predominaram os TTCGMNS (57,3%). Nestes, observou-se o predomínio de marcação para EGFR e c-Kit. O EGFR foi expresso quando o componente coriocarcinoma era predominante e o c-Kit no componente epitelial do teratoma. A hipótese do estudo, que os casos positivos para os marcadores analisados estariam correlacionados com sobrevida menor, não foi confirmada pela analise estatística de Kaplan-Meier; seria necessário um maior número de casos para se chegar a uma conclusão quanto à sobrevida. Superexpressão, amplificação gênica e mutações ativadoras são frequentes em tumores testiculares germinativos; deste modo, o uso da técnica de Hibridização Fluorescente in situ (FISH) foi utilizada para avaliação dos eventos gênicos relativos a imunoexpressão proteica, observada pelos resultados encontrados no estudo imuno-histoquímico. Somente um caso, classificado como TTCGM, apresentava amplificação para gene EGFR. Este caso apresentou bom prognóstico. Considerou-se que, a ausência de amplificação observada na maioria dos casos, deve-se a qualidade inadequada do material parafinado e estocado. Conclui-se que, na série estudada, os TTCGNS expressam os marcadores EGFR, Her2 e c-Kit, a depender do subtipo histológico; entretanto, estas proteínas não tiveram impacto prognostico. A amplificação gênica para o EGFR pode ocorrer de forma isolada, porem devido a condições técnicas restritivas, não foi possível observa-la nos demais casos positivos para EGFR pela técnica de imuno-histoquímico.
Testicular neoplasms constitute approximately 1% of male cancers. Among these, germ cell tumors (TGCT) are the most prevalent. These tumors show varied morphological patterns and are distributed into two subgroups: seminomas and non-seminomas. The latter, in turn, are classified as embryonal carcinomas, endodermal sinus tumors, choriocarcinomas, teratomas and mixed germ cell tumors. The consensus in the literature is that histological verification of vascular invasion (VI) in the primary tumor is the best predictor of disease progression and recurrence. However, recent studies have highlighted the role of growth factors and their receptors for prognostic evaluation of TGCT, in which the use of immunohistochemistry is fundamental. This study sought to evaluate the occurrence of epidermal growth factor receptor (EGFR), Her2 and c-Kit in a series of primary non-seminoma TGCTs. In addition, possible relationships between the expression of these markers and patient evolution following conventional therapy was investigated. The series consisted of paraffin-embedded samples from the Laboratory of Anatomical Pathology and Cytology of Amaral Carvalho Hospital in Jaú, SP, Brazil, of 103 patients diagnosed with testicular non-seminoma germ cell tumor (NSGCT) over a 15-year period (1996-2010). Among the 103 cases, testicular NSGCT predominated (57.3%), and among these, staining for EGFR and c-Kit predominated. EGFR was expressed when the choriocarcinoma component was predominant, and c-Kit when the epithelial component of the teratoma was predominant. The initial hypothesis that positive cases for any marker would be correlated to lower survival was not confirmed by Kaplan-Meier survival probability studies. A larger number of cases is required to reach any conclusions concerning survival. Gene overexpression and amplification and activating mutations are common in testicular germinal tumors, thus fluorescent in situ hybridization (FISH) was used to validate the genic events results obtained in the immunohistochemical study. Only one case, classified as mixed TGCT, showed EGFR gene amplification, and this case presented good prognosis. The lack of amplification observed in most cases was due to the inadequate quality of the stored, paraffinembedded materials. In conclusion, in the series studied, testicular NSGCT expressed EGFR, Her2 and c-Kit markers depending on the histological subtype; however, these proteins had no prognostic impact. Gene amplification for EGFR may occur in isolation, but due to the limited technical conditions, it was not observed in the other cases positive for EGFR using immunohistochemistry.
8
Quevedo, Francisco Carlos. "Tumores testiculares germinativos não-seminomas imunoexpressão protéica de EGFR, Her2 E c-Kit /." Botucatu, 2017. http://hdl.handle.net/11449/151631.
Full textAbstract:
Orientador: Maria Aparecida Custodio DominguesResumo: As neoplasias testiculares constituem aproximadamente 1% dos cânceres masculinos. Dentre eles, os tumores que têm origem nas células germinativas (TTCG) são os mais frequentes. Por sua natureza, esses tumores têm padrão morfológico variado, sendo distribuídos em dois subgrupos: os seminomas e os não-seminomas. Esses últimos, por sua vez, são classificados em carcinomas embrionários, tumores do seio endodérmico, coriocarcinomas, teratomas e tumores mistos de células germinativas. Há consenso na literatura de que a invasão vascular verificada histologicamente no tumor primário é o melhor indicador preditivo de progressão da doença e recidiva. Estudos recentes demonstram o papel dos fatores de crescimento e seus receptores para avaliação prognóstica dos TTCG, no que o uso da imuno-histoquímica é fundamental. O presente estudo procurou avaliar pela técnica imuno-histoquímica à ocorrência da expressão do receptor do fator de crescimento epidérmico (EGFR), do Her2 e do c-Kit em uma série de TTCG não-seminomas primários de testículo. Além disso, explorou a possível relação entre a expressão desses marcadores com a evolução dos pacientes após terapêutica convencional. A série foi constituída de amostras parafinadas existentes no Laboratório de Anatomia Patológica e Citologia do Hospital Amaral Carvalho de Jaú, totalizando 103 pacientes que receberam o diagnóstico de tumor testicular de células germinativas não-seminomas (TTCGNS) no período 1996-2010. Dentre os 103 casos, predominaram... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Testicular neoplasms constitute approximately 1% of male cancers. Among these, germ cell tumors (TGCT) are the most prevalent. These tumors show varied morphological patterns and are distributed into two subgroups: seminomas and non-seminomas. The latter, in turn, are classified as embryonal carcinomas, endodermal sinus tumors, choriocarcinomas, teratomas and mixed germ cell tumors. The consensus in the literature is that histological verification of vascular invasion (VI) in the primary tumor is the best predictor of disease progression and recurrence. However, recent studies have highlighted the role of growth factors and their receptors for prognostic evaluation of TGCT, in which the use of immunohistochemistry is fundamental. This study sought to evaluate the occurrence of epidermal growth factor receptor (EGFR), Her2 and c-Kit in a series of primary non-seminoma TGCTs. In addition, possible relationships between the expression of these markers and patient evolution following conventional therapy was investigated. The series consisted of paraffin-embedded samples from the Laboratory of Anatomical Pathology and Cytology of Amaral Carvalho Hospital in Jaú, SP, Brazil, of 103 patients diagnosed with testicular non-seminoma germ cell tumor (NSGCT) over a 15-year period (1996-2010). Among the 103 cases, testicular NSGCT predominated (57.3%), and among these, staining for EGFR and c-Kit predominated. EGFR was expressed when the choriocarcinoma component was predominant, and c-K... (Complete abstract click electronic access below)
Doutor
9
Goddard, Neil C. "Identification and role of activated receptor tyrosine kinases in testicular germ cell tumour subtypes of adolescents and adults." Thesis, Institute of Cancer Research (University Of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511166.
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Jostes, Sina Verena [Verfasser]. "The bromodomain inhibitor JQ1 as novel therapeutic option for type II testicular germ cell tumours / The role of SOX2 and SOX17 in regulating germ cell tumour pluripotency / Sina Verena Jostes." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1194464874/34.
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Hamada, Shota. "Antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor receiving 5-day cisplatin-based combination chemotherapy." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/192148.
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Published in Supportive Care in Cancer 2014;22(8):2161-6. DOI:10.1007/s00520-014-2182-7Kyoto University (京都大学)
0048
新制・課程博士
博士(社会健康医学)
甲第18548号
社医博第59号
新制||社医||8(附属図書館)
31448
京都大学大学院医学研究科社会健康医学系専攻
(主査)教授 武藤 学, 教授 佐藤 俊哉, 教授 千葉 勉
学位規則第4条第1項該当
12
Mishina, Mutsuki. "Equivalent Parental Distribution of Frequently Lost Alleles and Biallelic Expression of the H19 Gene in Human Testicular Germ Cell Tumors." Kyoto University, 1997. http://hdl.handle.net/2433/202161.
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Gutekunst, Matthias [Verfasser], and Peter [Akademischer Betreuer] Scheurich. "Chemosensitivity of testicular germ cell tumors is based on high constitutive Noxa protein levels and a functional p53 response / Matthias Gutekunst. Betreuer: Peter Scheurich." Stuttgart : Universitätsbibliothek der Universität Stuttgart, 2013. http://d-nb.info/1042442568/34.
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Camacho, Moll Maria Elena. "Germ cell neoplasia in situ (GCNIS) and the pathogenesis of testicular germ cell cancer." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28807.
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Testicular germ cell cancer (TGCC) has been increasing in incidence over recent decades, and is currently the most common malignancy amongst young men resulting in significant morbidity. These tumours are believed to arise from premalignant germ cell neoplasia in situ (GCNIS) cells, which originate from the aberrant germ cell differentiation from gonocyte to spermatogonia during fetal/early postnatal life. GCNIS cells remain dormant in the testis until puberty when they are activated to become tumours. Therefore, GCNIS cells remain in a pre-invasive stage during early childhood and early adulthood prior to the development of a seminoma or non-seminoma TGCC. GCNIS cells are phenotypically similar to gonocytes with expression of stem cell/early germ cell markers including OCT4, PLAP and LIN28. Furthermore, proteins which are expressed in more mature germ cells (spermatogonia) such as MAGE-A4 have also been shown to be expressed in GCNIS cells and these studies have indicated that GCNIS cells are a heterogeneous population in terms of protein expression profile. The relationship between the protein expression profile of individual GCNIS cells populations and their oncogenic potential has not been fully explored. GCNIS cells are located in the seminiferous tubules supported by somatic Sertoli cells. These cells have been previously reported to exhibit an immature protein expression profile in GCNIS tubules from patients with testis cancer, suggesting that the germ stem cell niche in GCNIS tubules resembles that of a fetal one. Associations between Sertoli cell maturation and GCNIS progression into tumour formation has not been fully investigated. Oncogenes are key players in the regulation of oncogenic potential of cancer cells. Gankyrin is an oncogene that has been shown to down-regulate OCT4, and interact with MAGE-A4 in hepatocellular carcinoma and colorectal cancer, where Gankyrin interaction with MAGE-A4 reduces the oncogenic potential of tumour cells. In this study I aimed to investigate the heterogeneity of GCNIS in relation to disease stage and Sertoli cell development. We also aimed to determine the role of Gankyrin in TGCC cell survival and invasion. The co-expression of early germ cells proteins such as OCT4, LIN28 and PLAP was characterized in GCNIS cells during childhood and adulthood pre-invasive TGCC and in invasive disease characterized by the presence of a testicular tumour. These results show that LIN28 was expressed in 95% of OCT4 GCNIS cells, whereas PLAP expression in GCNIS cells increased as the disease progressed from childhood pre-invasive disease to invasive seminoma (32.3% v 76%; p < 0.05). In contrast there was a reduction in the proportion of MAGE-A4 expressing GCNIS cells with disease progression. The MAGE-A4 expressing population was also less proliferative than the MAGE-A4 negative GCNIS population. The methylation status of GCNIS cells was then investigated. EZH2 a methyltransferase previously reported to be important for TGCC development, was expressed in GCNIS cells at all stages of disease, however the histone 3 modification H3K27me3 (mediated by EZH2) was expressed in a significantly higher percentage of the proliferative OCT4+/MAGE-A4- GCNIS cells compared with the OCT4+/MAGEA4+ population (11.7% v 1.1%; p < 0.01) which could indicate a repressive role for H3K27me3 over MAGE-A4 expression. Next, it was determined whether an association between Sertoli cell maturation status and progression of TGCC could be observed. The maturation status of Sertoli cells was studied using proteins indicative of immature (desmin, cytokeratin, fibronectin and AMH) and mature (vimentin and androgen receptor) Sertoli cells. These studies demonstrated heterogeneity of Sertoli cells maturation in GCNIS-containing tubules. Desmin, fibronectin, AMH and vimentin expression did not show any association with TGCC progression. Cytokeratin was expressed in Sertoli cells of human fetal testis up to second trimester of fetal life, absent in tubules with active spermatogenesis but heterogeneously present in GCNIS, demonstrating that cytokeratin expression is indicative of the presence of GCNIS. Androgen receptor was weakly present in Sertoli cells from human fetal testis and pre-pubertal pre-invasive TGCC testis whereas in GCNIS of adult pre-invasive testis and invasive samples, androgen receptor was abundantly expressed in Sertoli cells of GCNIS-containing tubules. These combined results for cytokeratin and androgen receptor suggest that Sertoli cells from GCNIS-containing tubules, in pre-invasive and invasive TGCC patients are partially differentiated. Gankyrin expression was characterised in fetal germ cells, GCNIS cells and TGCC tissue. In fetal testis nuclear Gankyrin was absent in OCT4+/MAGE-A4- (gonocyte) population whereas it was present in a subpopulation of OCT4-/MAGE-A4+ (spermatogonia) germ cells. In GCNIS cells from TGCC patients nuclear Gankyrin was expressed in 87%, 63.3%, 91.5% and 79% in childhood pre-invasive, adult pre-invasive, seminoma and non-seminoma GCNIS cells respectively. Finally, in seminoma cells, Gankyrin was expressed in the cytoplasm indicating a change in localisation as the GCNIS cells become invasive. We used siRNA to knockdown Gankyrin in NT2 (a TGCC cell line) cells in-vitro and demonstrated a decrease in cell number, suggesting that Gankyrin might play a role in TGCC progression and invasiveness. Gankyrin down-regulation also resulted in an increase in p53 and p21 mRNA level. Given the role of P53 and p21 in cisplatin cytotoxic effect in TGCC we went on to investigate the role of Gankyrin in cisplatin resistance using NT2 cells. We demonstrate that Gankyrin mediated cisplatin resistance through the p53/p21 pathway, upregulating apoptosis rates through BAX and FAS, whilst there was no effect on cell proliferation, cell cycle or cell migration. In conclusion, we have shown that GCNIS cells are heterogeneous and their phenotype can determine their oncogenic potential. We also show that Sertoli cells from GCNIS-containing tubules undergo partial differentiation displaying markers of immature and mature Sertoli cells, with a heterogeneous association of cytokeratin with GCNIS presence. We also demonstrate that the oncogene Gankyrin has a role in NT2 cells survival and cisplatin resistance indicating that manipulation of Gankyrin may have a role in the treatment of TGCC.
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Richiardi, Lorenzo. "New evidence on germ-cell testicular cancer aetiology /." Stockholm, 2003. http://diss.kib.ki.se/2004/91-7349-733-9/.
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Weir, Hannah Kate. "Endocrine factors and risk of testicular germ cell cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ28312.pdf.
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Goker, Hakan. "Molecular genetic analysis of adult testicular germ cell tumours." Thesis, Institute of Cancer Research (University Of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396014.
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Heninger, Noah Leland III. "The role of testicular germ cell apoptosis during equine spermatogenesis." Texas A&M University, 2005. http://hdl.handle.net/1969.1/4691.
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Apoptosis in testicular germ cells has been demonstrated in many species.
Features of apoptosis reported in other species were used to confirm use of the TUNEL
assay in stallion testes. Eight stallions with normal testicular size and semen quality were
evaluated to determine the germ cell types and stages where apoptosis most commonly
occurs. Mean numbers of TUNEL-positive germ cells per 100 Sertoli cell nuclei were
highest in stages IV and V of the seminiferous epithelial cycle corresponding to meiotic
divisions of primary spermatocytes and mitotic proliferation of B1 and B2
spermatogonia. Round and elongated spermatids were labeled less frequently by the
TUNEL assay.
To examine the relationships between germ cell apoptotic rate and spermatogenic
efficiency, seminal traits were assessed to classify stallions into normal or reduced
quality semen groups. Apoptotic rates were higher for stages IV-VI and stage VIII
seminiferous tubules in stallions with reduced semen quality. Daily sperm production
(DSP) per gram and per testis were lower for stallions with reduced semen quality. Regression analyses revealed negative linear relationships for germ cell apoptotic rate
with DSP/g, DSP/testis, daily sperm output, progressively motile sperm and
morphologically normal sperm in ejaculates. Mean circulating concentrations of inhibin
were lower for stallions ejaculating reduced quality semen. Apoptotic rate was
negatively correlated with concentrations of inhibin and estradiol-17b and positively
correlated with concentrations of LH and FSH.
To study germ cell apoptosis and formation of the Sertoli cell barrier during the
initiation of spermatogenesis, tubule development was classified based on lumen score.
Formation of a seminiferous tubule lumen was consistent with events leading to
development of a Sertoli cell barrier. A primary wave of apoptosis removed early
differentiating germ cell types prior to the formation of a tubule lumen facilitating both
the formation of a tubule lumen and a Sertoli cell barrier. A second wave of apoptosis
occurred after the formation of a lumen but before seminiferous tubule cross-sections
contained a full complement of germ cells.
In conclusion, apoptosis is an essential mechanism during normal spermatogenesis.
Apoptosis also accounts for low numbers of normal sperm seen in the ejaculates of some
stallions.
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Adamah, David Jackson Bukari. "An investigation into the genetic basis of testicular germ cell tumours." Thesis, University of Sheffield, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398405.
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Roewer, Jesse F. "CONSEQUENCE OF PREMATURE AND CHRONIC LUTEINIZING HORMONE RECEPTOR ACTIVATION ON TESTICULAR SPERMATOGENIC CELL DEVELOPMENT." OpenSIUC, 2010. https://opensiuc.lib.siu.edu/theses/253.
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Luteinizing hormone (LH), one of the two gonadotropin hormones released from the anterior pituitary gland, binds to its receptor (LHR) in the gonads to stimulate steroid hormone production, in addition to ovulation and gametogenesis. Mutations of the receptors amino acid sequence have the ability to either constitutively activate or inactivate it. All activating mutations result in male-limited precocious puberty. Males with this condition undergo puberty around 4 years of age, and have a premature elevation in testosterone levels and premature skeletal development. In order to understand how chronic ligand-mediated activation of the LHR affects gonadal development and function, a mouse model expressing a yoked hormone-receptor (YHR) complex, engineered by covalently linking the hormone human chorionic gonadotropin to the rat LHR, has been studied. YHR+ males have prepubertally elevated testosterone and decreased gonadotropin levels, smaller testis, and smaller average seminiferous tubule diameters when compared to wild type (WT) animals. In a preliminary breeding study it was shown that YHR+ males were sub-fertile. Based the phenotype exhibited by the YHR+ mice, it was hypothesized that increased levels of testosterone in addition to decreased gonadotropin hormone levels in neonatal and prepubertal mice that results from premature activation of the luteinizing hormone receptor causes spermatogenesis to be impaired. The first objective of this study was to determine if there was a difference in the testicular germ cell and Sertoli cell populations in the WT and YHR+ animals using flow cytometry and systematic Sertoli cell counting, respectively. There was no difference in the Sertoli cell population between YHR+ animals and WT controls, but there were significantly fewer total germ cells in YHR+ animals at 10 days and from 4 weeks through adulthood. The second objective was to calculate the daily sperm production in the testis and epididymis of WT and YHR+ animals in order to determine if there is a further decrease in the total sperm count due to an epididymal dysfunction. Interestingly, there were significantly fewer sperm calculated in the caput/corpus region of the epididymis in YHR+ males at 12 weeks of age, but not in the testis and cauda epididymis. Furthermore, the daily sperm production in WT and YHR+ mice at 16 weeks of age were not significantly different. The final objective was to determine if the decrease in germ cells observed in YHR+ animals is the result of decreased proliferation or an increase in either germ cell or Sertoli cell apoptosis. Quantification of germ cell and Sertoli cell proliferation revealed no significant difference between the WT and YHR+ animals. Similar findings were found after quantification of apoptotic germ cell and Sertoli cells. Taken together, these data suggest that premature elevation in testosterone and persistently lower levels of circulating follicle stimulating hormone (FSH) are affecting Sertoli cell function, which is causing a reduced germ cell to Sertoli cell ratio in the YHR+ mice. These data suggest that the decrease in testis weight and seminiferous tubule diameter in YHR+ mine is due to a decrease in germ cell rather than Sertoli cell number.
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Noel, Elodie Emilie. "Genetic investigation of the mechanisms of chemo-resistance in testicular germ cell tumours." Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497922.
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Resistance to chemotherapy has been reported in various malignancies and constitutes a major challenge in cancer care. Over the years, several pathways have been suggested in the literature, but the mechanisms behind resistance to treatment remain unclear. Testicular germ cell tumours (TGCTs), the most common malignancy in young men, are known for their extreme sensitivity to cisplatin-based chemotherapy and their excellent clinical outcome, making them an ideal tumour model for the investigation of cisplatin-induced sensitivity and resistance.
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Jafer, Osman. "Identifying genes involved in the progression of adult testicular germ cell tumours (TGCTs)." Thesis, Institute of Cancer Research (University Of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409508.
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Wang, Xianghong. "Investigations of the molecular basis of cisplatin sensitivity in testicular germ cell tumours." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300416.
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Zechel, Jennifer Lynn. "DEADEND1 GENETICS IN MOUSE MODELS OF TESTICULAR GERM CELL TUMOURS AND THEIR METASTASES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1372716917.
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Badcock, Graeme Leslie. "Characterisation of the TRA-1-60 antigen, a marker for testicular germ cell tumours." Thesis, University of Sheffield, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268286.
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McIntyre, Alan Joseph. "Identifying potential markers and targets for therapy in testicular germ cell tumours of adolescents and adults." Thesis, Institute of Cancer Research (University Of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434349.
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Lim, Jasmine. "Paternal age effect mutations in germ cell development : pathological correlates in normal testis and testicular tumours." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:da034844-3b4e-4bf8-a834-f0dea23e018b.
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Pathogenic gain-of-function mutations associated with increased paternal age, albeit harmful to embryonic development, are paradoxically enriched in the normal testis. Evidence from previous studies indicates that these so-called paternal age-effect mutations confer a proliferative advantage to the spermatogonia in which they arise, leading to clonal expansion within the normal testis over time. Recently, spermatocytic seminoma (SS; a rare testicular germ cell tumour that occurs mainly in older men) has emerged as a key link between the processes of somatic and germline mutation (Goriely et al, Nat Genet. 41:1247-52, 2009), suggesting that the proposed clonal expansion events can in some cases lead to testicular tumourigenesis. In this thesis, I have used immunohistochemistry to seek evidence for putative clones of cells in the normal adult testis. To address this, a screening approach was developed using markers chosen from analysis of normal testicular tissues and SS. The ontogeny of OCT2 and SSX expression in human testis, from embryonic development to adulthood, identified distinct subpopulations of spermatogonia at different maturation stages. Together, these data reveal the potential of OCT2 as a novel marker of Adark spermatogonia (human reserve spermatogonial stem cells). In parallel with these observations, two distinct types of SS characterised by differential OCT2 and SSX immunoexpression were identified, providing new evidence for heterogeneity of this tumour. This work provided the backdrop to the detailed immunohistochemical study of normal adult testis by characterising in serial sections the expression of five spermatogonial markers, MAGEA4, SSX, FGFR3, OCT2 and SAGE1, and a proliferation marker, Ki67. Independent sections were screened with predetermined criteria set to identify unusual positively-stained cellular clusters within the seminiferous tubules. Several antigenic combinations previously described in SS were observed in a subset of these clones, suggesting differing genetic origins and a possible link with early events of testicular tumourigenesis. The size (minimum number of cells) of each clonal event was estimated and its correlation with the staining pattern of the molecular markers was investigated. In summary, the data presented in this thesis convincingly identify for the first time the previously hypothesised clonal events in the testis using immunohistochemical markers. My research will pave the way for future work involving genetic analysis of microdissected cells from these putative clones, aimed at identifying the underlying mutational events thought to be present.
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Nguyen, Bryan. "Gene Expression Changes from Exposure to Phthalates in Testicular Cells." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22913.
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Phthalates are industrial plasticizers with a wide range of applications. Di-(2-ethylhexyl) phthalate (DEHP) is one of the most highly produced and frequently studied phthalates. Its metabolite, mono-(2-ethylhexyl) phthalate (MEHP) is known as a testicular toxicant. The objective of this study was to examine expression of the genes of interest in testicular germ cells exposed to MEHP in a dose- and time-dependent manner at concentrations of 1µM, 10µM, and 100µM at 24, 48, 72 and 96hr time points. The genes consisted of Testisin, GSPT1, and MGMT genes which are a tumor suppressors, phase II xenobiotic metabolizing enzyme and DNA repair gene respectively. These genes were analyzed by Quantitative Real Time PCR (RT-PCR). The results revealed an overall down-regulation for each gene as the concentration and/or time increased. Testisin was the focus of the gene expression analysis. Testisin is epigenetically silenced in testicular germ cell tumors (TGCT) by DNA methylation at the 5’CpG island of the gene. To investigate if MEHP is capable of DNA hypermethylation, a co-exposure with 5-azacytidine (demethylating agent) was conducted. Compared with the 5-azacytidine treatment alone, there was a significant down-regulation of the Testisin gene in the co-exposure. This suggests that MEHP may down-regulate Testisin gene expression by DNA methylation. These findings provide evidence that MEHP can alter the expression of Testisin, GSTP1 and MGMT, genes that are associated in the risk of developing testicular germ cell tumors. In addition, results indicated that MEHP may cause DNA methylation leading to the down-regulation/silencing of genes such as Testisin.
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Schirmer, Sylvia [Verfasser]. "Expression profile of components of the acetylcholine-system in rat testicular tissue and function in non-germ cell populations / Sylvia Schirmer." Gießen : Universitätsbibliothek, 2011. http://d-nb.info/1063048842/34.
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Gilbert, Duncan. "Identification of markers for relapse and candidate genes for involvement in the progression of stage I non-seminomatous testicular germ cell tumours." Thesis, Institute of Cancer Research (University Of London), 2009. http://publications.icr.ac.uk/10311/.
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Testicular germ cell tumours (TGCT) are the commonest solid tumour to affect young adult males and are increasing in incidence for reasons poorly understood. 60% of the non-seminomatous (NS) subtype present with stage I disease (clinically localised to the testes). Although apparently cured by surgery alone, up to 50% will subsequently relapse through the presence of micrometastases. Adjuvant chemotherapy reduces the relapse rate to 2%, but is associated with acute toxicity and long-term side effects (second cancers and an increased risk of cardiovascular disease) and represents unnecessary treatment for at least half of these patients. Histological evidence for vascular invasion is currently used as an indicator of subsequent relapse but is inaccurate and therefore improved prognostic markers are urgently required. In order to identify genomic regions associated with likelihood of relapse, full tiling path resolution BAC array comparative genomic hybridisation was used to characterise formalin fixed, paraffin embedded material from 32 stage I NS, 15 of which were known to subsequently relapse. Published expression microarray data from TGCT was then used to identify gene expression patterns from the genomic regions identified. This identified candidate genes as markers of relapse as well as supporting the importance of RAS and PI3 kinase signalling in TGCT. In addition, the expression levels of known mediators of metastatic dissemination were identified as further candidates for involvement in TGCTs. Genomic data demonstrated loss of 22q12.2 (containing DRG1 and PIK3Ip1) and gain of 22q13.32 (BRD1) being associated with relapse and a cluster of cytokines on 17q12 associated with vascular invasion. These genes were investigated using immunohistochemistry on a tissue microarray constructed from 83 stage I NS with known clinical outcomes. Candidates selected on the basis of the expression data and their potential functional role were VEGF-A, MMP2, MMP9 and the chemokine CXCL12 and its receptor CXCR4. Variable rates of expression of VEGF-A, MMP2 and MMP9 were identified though no correlations with subsequent clinical behaviour found. Universal expression of the chemokine receptor CXCR4 by TGCT was demonstrated, with autocrine expression of the ligand CXCL12 associated with a reduced rate of subsequent relapse (p=0.003) indicative of a significant prognostic marker. This could be explained by low intratumoural expression of CXCL12 mediating migratory behaviour. Consistent with this hypothesis, functional work using TGCT cell lines demonstrated CXCR4 mediated migration towards CXCL12 gradients, with concurrent activation of ERK1/2. Based on this study, work to validate CXCL12 as a clinically useful prognostic marker in stage I NS is warranted and currently underway using samples from patients treated and monitored in a clinical trial setting.
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Shah, Rachana M. D. "Dysgerminoma in Children, Adolescent and Young Adults: A Report from the Malignant Germ Cell Tumor International Collaborative (MaGIC)." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505123966588768.
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Dean, Afshan. "Androgens and the masculinisation programming window." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6516.
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The commonest reproductive disorders of young men (namely low sperm counts, testicular germ cell cancer) may originate in fetal life similar to established disorders (cryptorchidism, hypospadias) that manifest at birth. These disorders are interlinked and may comprise a testicular dysgenesis syndrome (TDS), a concept supported by animal model studies. The latter have identified the likely time-frame within which TDS disorders may be induced, namely within the so-called masculinisation programming window (MPW). During this critical period, sufficient testosterone (androgen) must be produced by the fetal testis to program the male reproductive tract so that it will differentiate and grow normally after the MPW. Impaired androgen production or action within the MPW can result in smaller reproductive organs and their abnormal formation and function (e.g. cryptorchidism, hypospadias). The MPW is thus of fundamental importance in determining normal, or abnormal, male reproductive development and function for later life. There are two big unanswered questions about the MPW. First, what determines its timing? Second, what mechanisms are controlled by androgens specifically within this time-window and not at later time points? Three approaches were undertaken to address the first question experimentally in rats. First, investigation of whether the availability of androgens and or androgen receptors (AR) plays a role in determining the onset or ‘opening’ of the MPW. Second, investigation of whether the expression of AR co-regulators was a factor in determining androgen sensitivity during the MPW. Third, investigation of whether prostaglandins played a role in mediating androgen action in the MPW, as studies in the 1980s had suggested this possibility. To address what mechanisms are controlled by androgens specifically within the MPW, the expression of selected genes in the genital tubercle was investigated before, during and after the MPW in fetuses that had been exposed to treatments that modulated androgen action. Selection of genes was based on microarray studies and data reported in the literature (ie candidate genes). The studies reported in this thesis show that neither availability of androgens nor the AR are important in determining onset of the MPW, and providing exogenous androgens either prior to or during the MPW does not advance or enhance masculinisation. These studies also showed that females may have a slightly different window of susceptibility to androgen action than do males. Key AR co-regulators have been characterized in the male reproductive tract for the first time, two of which (BRG1, CBP) show changes in expression through development of the testis consistent with a role in Sertoli cells. Another AR co-regulator, RWDD1, was found to switch off in the absence of androgen action in the genital tubercle, pointing to a potential role during and/or after the MPW. Studies involving gestational exposure to indomethacin (a compound which inhibits prostaglandin synthesis) during the MPW showed no detectable effect on masculinisation. Finally, evaluation of candidate genes for mediating androgen action in the genital tubercle during the MPW, failed to identify their key involvement, thus they are unlikely to be involved in penis development and disorders such as hypospadias.
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Dabare, Abeysinghe Arachchige Nandike Prashanth M. "Development of new monoclonal antibodies and colorimetric assays for improved detection of testicular germ cell tumours (TGCTs) and determining the relevance of over-expressed P53 in TGCT sensitivity to treatment." Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312172.
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Rick, Oliver. "Therapieoptimierungsverfahren bei Patienten mit rezidivierten oder progredienten Keimzelltumoren." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2004. http://dx.doi.org/10.18452/13921.
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Patienten mit metastasierten Keimzelltumoren, die einen Progress oder ein Rezidiv ihrer Erkrankung nach einer cisplatinhaltigen Vortherapie erleiden, haben eine schlechte Prognose. Unter Verwendung einer erneuten konventionellen Chemotherapie können maximal 15-30% dieser Patienten geheilt werden, so dass die Mehrzahl der Patienten an ihrer Erkrankung verstirbt. Aus diesem Grund ist die Optimierung der therapeutischen Möglichkeiten ein wesentliches Ziel. Unsere Daten zeigen, dass die Hochdosischemotherapie (HDCT) eine wesentliche therapeutische Verbesserung darstellt und mittels dieser Therapie mit einem ereignisfreien Überleben von 30-60% zu rechnen ist. Eine "matched-pair" Analyse konnte im Hinblick auf das ereignisefreie und das Gesamtüberleben einen Vorteil von mehr als 10% zu Gunsten der HDCT feststellen. Darüber hinaus hat die zunehmende Erfahrung und die Verwendung von peripheren Blutstammzellen und hämatopoetischen Wachstumsfaktoren, den Einsatz der HDCT deutlich sicherer gemacht. Aus den genannten Gründen sollte alle Patienten mit Rezidiv oder Progress eines Keimzelltumors der HDCT zugeführt werden. Die operative Entfernung von residuellen Tumormanifestationen (RTR) nach primärere Chemotherapie ist heute Standard bei Patienten mit metastasierten Keimzelltumoren. Zwar findet sich in der histologischen Aufarbeitung bei den meisten Patienten ausschließlich nekrotisches Gewebe, doch werden bei einem Teil der Patienten auch Anteile von reifem Teratom und vitalen differenzierten und undifferenzierten Karzinomen gefunden. Während die Resektion von Nekrose keinen therapeutischen Benefit für den Patienten darstellt, ist die komplette Entfernung von reifem Teratom oder Zellen eines Karzinoms für die Prognose entscheidend. In Bezug auf die HDCT konnten bisher keine vergleichbaren Daten erhoben werden. Zur Evaluierung des Stellenwertes der RTR nach HDCT analysierten wir unser eigenes Patientenkollektiv und fanden, dass vergleichbar zur Primärtherapie alle Patienten nach Salvage-HDCT, die eine partielle markernegative oder markerpositive Remission erreicht haben, einer RTR zugeführt werden sollten. Bis auf intrazerebrale Reste sollten alle residuellen Tumormanifestationen komplett reseziert werden. Neben der Optimierung der therapeutischen Möglichkeiten ist auch die Minimierung der chemotherapieassoziierten Toxizitäten ein wesentlicher Bestandteil meiner wissenschaftlichen Arbeit. Aus diesem Grund evaluierten wir die Wirksamkeit der Substanz Amifostin im Hinblick auf die Verringerung von Toxizitäten, die Wirkung auf die Mobilisierung von peripheren Blutstammzellen und den Einfluß auf die Rekonstitution des Immunstatus bei Patienten mit rezidivierten oder progredienten Keimzelltumoren, die mittels einer konventionellen Chemotherapie und anschließender HDCT behandelt wurden. Der Einsatz von Amifostin erbrachte in diesem Zusammenhang und in diesem Patientenkollektiv keinen therapeutischen oder prophylaktischen Nutzen, so dass dessen Verwendung bei Patienten mit Keimzelltumoren nicht generell empfohlen werden kann.Overall, patients with relapsed or progressive germ cell tumors (GCT) after cisplatin-based chemotherapy have a low chance of cure. Using conventional-dose chemotherapy as salvage treatment only 15-30% of the patients will become long-term survivors. It is well known that the majority of these patients will ultimately die of their disease. Therefore, improvment of standard treatment is clearly desirable. Our data has been established high-dose chemotherapy (HDCT) as an effective salvage modality with an event-free survival of 30-60%. A matched-pair analysis showed an advantage for HDCT compared with conventional-dose chemotherapy with improvement in event-free and overall survival of more than 10%. Furthermore, due to increasing clinical experience in the management of side-effects, the use of peripheral blood progenitor cells, and the availability of hematopoietic growth factors, HDCT has become relatively safe. In GCT patients with relapsed or rogressive disease HDCT has been demonstrated as a feasible and safe treatment concept which will be curative for a substantial proportion of these patients. Therefore, HDCT should be administered in patients with first relapse and unfavorable prognostic factors and as second or subsequent salvage treatment. Surgical resection of residual tumors (RTR) after first-line chemotherapy is recommended in patients with metastatic GCT. Necrosis will be the only histological finding in the majority of these patients. However, in others mature teratoma, viable cancer consisting of residual GCT, non germ-cell tumors, undifferentiated cancer or a combination of these histologies may be found. Whereas the resection of necrosis offers no therapeutic benefit, resection of mature teratoma or viable cancer adds to long-term event-free and overall survival in these patients. However, limited data exist on the results of surgery and the respective histologies in patients after first or subsequent salvage treatment with HDCT. To assess the contribution of RTR in this setting, we retrospectively analyzed a cohort of patients who had been treated with HDCT for relapsed or refractory GCT. Our data show that RTR contributes to the overall treatment outcome and should be offered to all patients with a partial remission after HDCT. Complete resections of all residual tumors outside the CNS should be attempted. Furthermore, we assessed the efficacy of amifostine for protection from chemotherapy-induced toxicities, for peripheral blood progenitor cell mobilization and for immune-reconstitution in patients treated with conventional-dose paclitaxel, ifosfamide, cisplatin (TIP) and high-dose carboplatin, etoposide and thiotepa (CET) followed by PBPC rescue. In conclusion, amifostine additional to conventional-dose chemotherapy or HDCT showed no unequivocal advantage in protection from treatment-related toxicities and had no effect neither on PBPC mobilization nor on immune-reconstitution.
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Beyer, Jörg. "Hochdosischemotherapie bei Patienten mit rezidivierten und refraktären Keimzelltumoren Etablierung und Optimierung eines neuen Therapieverfahrens." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2000. http://dx.doi.org/10.18452/13707.
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Rezidivierte und refraktäre Hodentumoren waren bis zu Beginn der 80er Jahre nur selten kurativ behandelbar. Mit Einführung der Hochdosischemotherapie in Verbindung mit autologer Stammzellreinfusion, konnte eine kurative Behandlungsoption auch in dieser prognostisch ungünstigen Situation in der Klinik etabliert werden. Die vorliegende Arbeit beschreibt die Ergebnisse der ersten Phase I/II Studie zur klinischen Etablierung dieses Therapieverfahrens ebenso wie verschiedene nachfolgende Untersuchungen zur Optimierung der Hochdosischemotherapie. Eine "matched-pair" Analyse konnte zumindest im retrospektiven Vergleich, den Nutzen dieses neuen Therapieverfahrens im Vergleich zu einer konventionell-dosierten Behandlung belegen.Until the beginning of the 1980ies relapsed and refractory germ-cell tumors were rarely cured. With the introduction of high-dose chemotherapy in combination with autologous stem cell reinfusion, a curative treatment option could be established in this prognostically unfavorable situation. The present work describes the results from the initial phase I/II studies that established this new treatment as well as the results of several subsequent trials to optimize this new procedure. Finally, the results of a "matched-pair" analysis is presented that demonstrates the superiority of this new treatment as compared to conventional-dose chemotherapy.
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Le, Cornet Charlotte. "Évolution du cancer du testicule en Europe : expositions environnementales et professionnelles." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10277/document.
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Les tumeurs germinales du testicule (TGT) représentent le cancer le plus fréquent chez les hommes Européens âgés de 15 et 39 ans. L'incidence a doublé dans la plupart des pays Européens depuis 30 ans. Cette augmentation rapide, les variations géographiques d'incidence et les études chez les populations migrantes suggèrent un rôle des facteurs environnementaux dans le développement des TGT. Cette thèse propose de contribuer à l'amélioration des connaissances concernant l'évolution du TGT en clarifiant l'impact des expositions environnementales et professionnelles, notamment pendant la période prénatale. Les objectifs principaux sont de: 1. Prédire l'incidence du TGT jusqu'en 2025 en estimant la part d'augmentation due aux changements démographiques afin d'obtenir une estimation de l'augmentation due aux risques. 2. Faire un bilan de l'état des connaissances sur l'association entre les expositions environnementales et professionnelles et le développement du TGT dans une revue systématique de littérature 3. Investiguer l'association entre l'exposition parentale professionnelle aux pesticides en période prénatale et le TGT parmi la descendance Les résultats montrent que l'incidence du TGT continue d'augmenter, mettant en avant un fort impact environnemental dans l'évolution du TGT. Néanmoins, la revue de littérature ne permettait pas d'identifier de facteurs de risque environnementaux avérés, mais montrait un manque d'études investiguant les expositions prénatales sur le risque de TGT. L'étude NORD-TEST menée sur les données de registre de quatre pays nordiques est l'étude la plus puissante à ce jour et ne montre aucune association entre l'exposition parentale professionnelle aux pesticides en période prénatale et le TGTTesticular germ cell tumours (TGCT) are the most common cancer diagnosed among young European men aged between 15 and 39 years. TGCT incidence rates have doubled in most European countries over the last 30 years. This rapid increase in incidence, the geographical variations and the studies in migrant populations suggest a role of environmental factors in TGCT aetiology. This thesis aims to contribute to the knowledge of TGCT evolution by studying the impact of environmental and occupational exposures, especially during the prenatal period. The objectives are: 1. To estimate the proportion of the increased incidence due to overall changes in risk patterns compared to the proportion due to demographic changes, by predicting the future testicular cancer trends in Europe 2. To summarize and evaluate the current knowledge on environmental and occupational exposures related to TGCT risk by means of a systematic literature review 3. To investigate the association between the prenatal parental occupational exposure to pesticides and TGCT risk in the offspring. The results show that the TGCT incidence continues to increase, supporting an environmental impact on TGCT evolution. From the epidemiological literature to date no specific environmental risk factors emerge; however, there have clearly been a lack of studies investigating prenatal exposures on TGCT risk. The NORD-TEST study, based on registry data from four Nordic countries, is the largest study to date. No association was found between parental occupational exposure to pesticides during prenatal period and TGCT risk
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Nabavi, Roya. "Zur Problematik der Spätrezidive von Hodentumoren." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15337.
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Welche Ursachen führen bei Keimzelltumoren zu Spätrezidiven? Sind es ungünstige Tumorkonstellationen, Behandlungsfehler oder individuelle Faktoren, die zu Spätrezidiven von Keimzelltumoren (KZT) führen? Ziel der Untersuchung war es, diese Fragen zu beantworten, um Patienten zu identifizieren, für die sich daraus Konsequenzen in der Therapie und Verlaufskontrolle ergeben. Indem wir Spätrezidive nach 4 Jahren auswerteten, wollten wir die besonderen Merkmale dieser Patientengruppe herausarbeiten. Unter 759 erfassten Patienten sahen wir 165 Frührezidive (< 2 Jahre), 92 Rezidive nach 2 Jahren und 73 Spätrezidive mehr als 4 Jahre nach der Initialdiagnose. Unsere statistische Auswertung bezieht sich auf die Spätrezidive mit einer mittleren Beobachtungszeit von 143 Monaten. Die initiale Konstellation der Tumormarker spielt eine bedeutende Rolle. 66% der Patienten hatten sowohl AFP als auch ß-HCG erhöht (gegenüber 47% bei den Frührezidiven und 33% im Gesamtkollektiv). Das gonadal reine Embryonalzellkarzinom (EZK) führt häufiger zu Spätrezidiven als andere Keimzelltumoren. Risikobehaftet sind höhere Stadien, von denen sich unter den Spätrezidiven 85% fanden; initial aber nur 57%. Demgegenüber ist poor-prognosis nach IGCCCG kein Risikofaktor. Mehr als die Hälfte der spätrezidivierten Patienten hatte bereits vorher mindestens ein Rezidiv gehabt. Eine initial von der heutigen Leitlinie abweichende Behandlung war bei 40% der Spätrezidive zu finden. Gründe hierfür waren eine falsche Histologie, die ungenaue Stadienzuordnung oder eine fehlende bzw. inkomplette Residualtumorresektion. Eine günstige Prognose haben die Patienten, bei denen eine Metastasenresektion vorgenommen werden kann. Die Heilungsrate (NED) war bei den operierten Spätrezidiven (70%) deutlich hoher als denjenigen, die zusätzlich chemotherapiert (46%) oder lediglich mit Chemotherapie behandelt worden waren (36%). Als Grund hierfür, ist die Früherkennung und noch vorhandene Operabilität des Befundes anzunehmen. Alle Seminom-Spätrezidive mit initialer Radiatio haben von der Chemotherapie profitiert. Bis auf einen Todesfall in der Chemotherapie wurden alle geheilt. Spätrezidive von KZT sollten als besondere Entität definiert werden. Krankheitsverlauf, Behandlung und Nachsorge weichen von dem üblichen Muster ab. Nur Seminome oder chemonaive Patienten sind zytostatisch zu behandeln. Bei den Nichtseminomen, die bereits initial oder im Frührezidiv eine Chemotherapie erhalten haben, sollte wenn möglich, eine operative Behandlung erwogen werden. Patienten mit initial erhöhten Tumormarkern (AFP + ß-HCG), reinem gonadalem EZK, höheren Krankheitsstadien oder einem Rezidiv innerhalb der ersten 4 Jahre haben eine ungünstige Prognose und erfordern eine jährliche lebenslange spezielle Nachsorge. Die Nachsorge sollte neben der klinischen Untersuchung und AFP-Bestimmung ein Schnittbildverfahren des Thorax und Retroperitoneums beinhalten.What are the reasons for late relapse of testicular germ cell tumor? Do unfavourable tumor constellations, mismanaged treatment or individual factors; lead to the late relapse of testicular germ cell tumor? The aim of this investigation was to find an answer to this question and to identify the patients, who would benefit from modified treatments and follow-up modalities. By researching the late relapses diagnosed at least 4 years later, we wanted to identify the special characteristics of this group of patients. Among the 759 patients with testis cancer we found 165 early relapses (
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Fröhner, Michael, Oliver W. Hakenberg, and Manfred P. Wirth. "Molecular Therapy in Urologic Oncology." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133789.
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During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignanciesDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Fröhner, Michael, Oliver W. Hakenberg, and Manfred P. Wirth. "Molecular Therapy in Urologic Oncology." Karger, 2007. https://tud.qucosa.de/id/qucosa%3A27535.
Full textAbstract:
During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Fresneau, Brice. "Analyses pronostiques en oncologie pédiatrique : Identification de facteurs de susceptibilité tumorale ou individuelle à l’efficacité et/ou à la toxicité des traitements anticancéreux utilisés chez l’enfant Investigating the Heterogeneity of Alkylating Agents' Efficacy and Toxicity Between Sexes: A Systematic Review and Meta-Analysis of Randomized Trials Comparing Cyclophosphamide and Ifosfamide (MAIAGE Study) Is Alpha-Fetoprotein Decline a Prognostic Factor of Childhood Non-Seminomatous Germ Cell Tumours? Results of the French TGM95 Study New Insight into Severe Ototoxicity after Childhood Cancer. Is there an Impact of Melphalan and Busulfan? A French Childhood Cancer Survivor Study A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated with High-Dose Methotrexate: Data from the OS2006/Sarcoma-09 Trial." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS034.
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Les progrès thérapeutiques en oncologie pédiatrique ont permis une amélioration des taux de survie qui dépassent aujourd’hui 80%. De façon à augmenter les taux de guérison et diminuer les complications et séquelles des traitements, des efforts collaboratifs internationaux ont permis le développement de protocoles thérapeutiques stratifiés sur les facteurs pronostiques majeurs incluant des facteurs biologiques tumoraux issus des analyses moléculaires et notamment génomiques. Cependant, si les traitements utilisés prennent de plus en plus en compte la biologie tumorale, leur adaptation aux facteurs individuels reste marginale. La thèse ici présentée cherche à mieux comprendre comment les caractéristiques tumorales et individuelles des patients modifient l’efficacité et la toxicité des thérapeutiques anticancéreuses utilisées en oncologie pédiatrique.Plusieurs travaux ont été réalisés :1- Etude de l’impact pronostique des facteurs tumoraux : évaluation de l’impact pronostique de la décroissance du marqueur tumoral alphafoetoprotéine (AFP) dans les tumeurs germinales malignes de l’enfant et de l’adolescent traitées par chimiothérapie ; 2- Etude de l’impact pronostique des facteurs constitutionnels : (i) évaluation de l’effet du sexe sur l’efficacité et la toxicité des agents alkylants ; (ii) évaluation de l’impact pronostique de polymorphismes génétiques de gènes impliqués dans le métabolisme du méthotrexate sur l’efficacité et/ou la toxicité du méthotrexate haute dose dans le traitement de l’ostéosarcome ;3- Etude des facteurs de risque de toxicité tardive : analyse de la de toxicité auditive sévère dans la cohorte des survivants à long terme de cancers pédiatriques (FCCSS)Therapeutic advances in pediatric oncology have improved survival rates reaching over 80%. In order to increase cure rates and decrease complications and treatment sequelae, international collaborative efforts led to the development of therapeutic trials stratified on major prognostic factors including biological factors. However, treatment adaptation to individual patient characteristics remains marginal.In this thesis, our objective was to better understand how somatic (tumor-related) and constitutional (patient-related) characteristics could modify efficacy and toxicity of anticancer therapies used in pediatric oncology. Several works were performed: 1- Prognostic analysis of tumor markers: assessment of the alpha-foetoprotéine (AFP) decline prognostic value in childhood malignant germ cell tumors; 2- Prognostic analysis of constitutional factors: (i) assessment of the interaction between gender and type of alkylating agents on efficacy and acute toxicity; (ii) assessment of the efficacy and toxicity impact of genetic polymorphisms in patients with osteosarcoma treated with high-dose methotrexate; 3- Risk factors analysis of long-term toxicities: analysis of severe ototoxicity in the French Childhood Cancer Survivors Study (FCCSS)
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Rosta, Viktória, and Csilla Krausz. "Comprehensive analyses of genetic and clinical factors in patients affected by Testicular Germ Cell Tumor." Doctoral thesis, 2022. http://hdl.handle.net/2158/1263662.
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Introduction: Testicular Germ Cell Tumor (TGCT) is a multifactorial, polygenic, and complex disease. It is the most common malignancy of men in their reproductive ages. This neoplasm has one of the highest heritability (37–48,9%) based mainly on epidemiological and Genome-Wide Association Study data. Epidemiological studies support that there is an increased familial cancer risk among TGCT patients’ family members. However, the studies are heterogeneous and sometimes controversial. Despite of the growing body of evidence regarding the involvement of genetic factors in TGCT susceptibility, our knowledge about its genetic basis remains scarce. In the latest study, aiming at the evaluation of 48 established DNA Repair (DR) genes in the etiopathogenesis of TGCT, CHEK2 has been identified as a new susceptibility gene with moderate penetrance. In addition, in a recent case report, TGCT has been linked to Lynch syndrome.
Objectives: In order to identify new clinical and genetic risk factors of TGCT, and to explore whether TGCT may be part of a more generalized cancer predisposition, we performed two projects: i) an epidemiological study, where we aimed to estimate the familial cancer risk among TGCT patients’ relatives (first-degree and grandparents), and ii) Whole Exome Sequencing (WES) in TGCT patients with positive family history of cancers, to identify monogenic causes of the malignancy and to determine the role of DR genes in the etiopathogenesis of TGCT.
Materials and Methods: For both projects included in this thesis, the patients were recruited at the Andrology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Centre of Excellence DeNothe, University of Florence, Florence, Italy and at the Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Spain.
In the epidemiological study, which was a multicentric, retrospective, case-control study, a total of 1407 subjects were enrolled. Among them, 592 were affected by TGCT, 352 had oncohematological (OH) malignancy, and 463 were fertile cancer-free controls. Statistical analyses were performed using SPSS Software.
In the second project, WES was carried out for 32 TGCT and one Leydig tumor patients, who had two or more family members affected by any type of malignant tumors. DNA was extracted form peripheral blood lymphocytes and WES was performed by NovaSeq 6000 System (Illumina) using the SureSelect Human All Exon V6 (Agilent Technologies) kit. After filtering for rare (Minor Allele Frequency < 0,01), presumed as deleterious, non-synonymous and splicing variants, we performed a first cross with 653 DR genes, and a second cross with 1731 Mendelian autosomal dominant genes from OMIM and COSMIC databases. For further classification of the variants’ pathogenicity, we used the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) criteria. Finally, a series of bioinformatic analyses were carried out.
Results: In the first, epidemiological study we found that TGCT patients’ relatives have significantly more cancers (p value = 0,0001) than controls’ relatives. As comparing the TGCT cohort with another type of malignancy, such as OH, which affects young males, we did not observe significant differences. This implies that OH patients also have an increased familial cancer risk (p value = 0,0045). Furthermore, we report some site-specific associations, other than TGCT aggregation in case of familial TGCT, and OH malignancy aggregation in case of familial OH. The novelty of our study is that we defined the semen phenotype for all subjects of the different cohorts, thus we were able to assess not only the impact of tumors versus non-tumors on familial incidence of neoplasms but also to compare whether non-normozoospermic subjects have more tumors among family members. We report a 1,57-fold higher risk (p value = 0,0048) for tumor development among family members if the patient had severe spermatogenic disturbances (azoospermia and severe oligozoospermia with TSC < 5 million). Another interesting finding of our study was that we observed significantly less siblings among TGCT (mean number of siblings: 1,16) and OH (1,09) cases in respect to controls (2,07).
In the WES study, we identified rare, predicted as damaging, germline variants of DR genes in 5 out of 32 (15,6 %) TGCT patients. We report seven variants in seven genes in the five subjects. Five out of 7 variants were loss-of-function, whereas two were missense. Three variants were classified as pathogenic, two as likely pathogenic, and two as “hot” VUS, according to ACMG criteria classification. Our main findings are related to Lynch syndrome (LS). We found mutations in three established LS genes (MSH6, MLH3, MLH1) in three patients with typical LS-associated tumor types among their relatives. The other mutated genes are involved in homologous recombination (FANCD2, XRCC3), nucleotide excision repair (ERCC3), and oxidative DNA damage repair (MUTYH). Further important finding of our study was the identification of two patients, both carrying two variants in different DR genes and presenting typical tumor types for both genes among their family members.
Conclusions and wider implications: Our results show association between TGCT, increased familial cancer incidence, and sub/infertility. Therefore, there might be a common link between spermatogenic defects and a systemic problem leading to higher morbidity including cancer development. The biological explanation for such a relationship could be an overall genomic instability/DNA repair defects in the family, which is reflected in the occurrence of multiple cancers and subfertility.
WES is a powerful tool for searching monogenic causes of TGCT in highly selected patients as it has been in our study on selected TGCT patients with family aggregation of cancers. DR genes might have a role in the etiopathogenesis of TGCT, which could explain the increased frequency of cancers among TGCT patients’ relatives. We therefore suggest to perform sequencing of DR genes in selected TGCT cases with clear signs of familial predisposition to cancer. We also propose that TGCT may be part of the Lynch syndrome associated urological malignancies. Therefore, an onco-andrological screening is suggested for the male members of Lynch syndrome families. On the other hand, in case of pathogenic variants in DR genes, other types of malignancies could occur later in life, hence a careful follow-up of these patients is strongly advised.
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Wu, Yu-Chih, and 吳友志. "Role of Homeobox Gene Oct-4 in Human Testicular Germ Cell Tumors." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/17590395488441584698.
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碩士臺北醫學大學
醫學研究所
94
Testicular germ cell tumors (TGCTs) are the most common malignant neoplasms of testis in men at ages of 15-34 years. TGCTs are histologically classified into seminoma and non-seminoma, or combination of the two types. Seminoma and embryonic carcinoma (non-seminoma) have been shown to exhibit a unique pattern of gene expression same as embryonic stem cells (ES), such as Oct-4. In ES, Oct-4 protein is known to be the master regulator to participate in controlling stem cell self-renew and differentiation. In seminoma and embryonal carcinoma, Oct-4 protein was also recognized as a diagnosis marker recently; however, the role of Oct-4 protein in germ cell tumor has not been clarified. To characterize the role of Oct-4 in germ cell tumorigenesis, we examined the expression pattern of Oct-4 protein in TGCTs. In this thesis, by collection patient’s tissues, NCCIT and NT2 cell lines and using immunohistological staining and Western blotting, we demonstrated the Oct-4 protein is highly expressed in human seminoma and embryonic carcinoma. Interestingly, the localization of Oct-4 protein in these tumor cells is not only in nucleus but also in cytoplasm. Furthermore, we demonstrated the relative expression level of Oct-4 mRNA among hES, NCCIT and NT2 cell lines by quantitative PCR; and the DNA methylation profile of the 5’-upstream region of the Oct-4 gene (-1069～-776 and -623～-356) was also examined by methylation specific PCR.
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Salgueiro, Bárbara Denise Vilela. "miR-371a-3p as a tool for subtyping Testicular Germ Cell Tumors." Master's thesis, 2018. http://hdl.handle.net/10348/8367.
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Os tumores de células germinativas testiculares (TGCTs) constituem um grupo heterogéneo de neoplasmas, afetando na maioria homens em idade jovem. As taxas de cura são elevadas e o tratamento adequado depende de uma avaliação clínica e patológica que seja cuidadosa e precisa. De fato, a subtipagem histopatológica dos TGCTs é um ponto crítico para uma decisão terapêutica adequada. Considerando a limitação dos biomarcadores de soro atualmente disponíveis, foram propostos novos candidatos, principalmente o miR-371a-3p, que superou os marcadores de soro clássicos, contudo não existe informação detalhada relativamente ao perfil de expressão nos vários subtipos de TGCTs. Deste modo, avaliamos os níveis dos níveis de expressão do miR-371a-3p nos vários subtipos de TGCT usando uma coorte consecutiva de amostras de tecido testicular. Após o isolamento do RNA e síntese de cDNA, os níveis de expressão do miR-371a-3p foram avaliados em 154 amostras de tecido de TGCT e em 15 tecidos não-tumorais por PCR quantitativo em tempo real (RT-qPCR). A fim de gerar uma curva padrão para a quantificação relativa e verificar a eficiência do PCR, o cDNA do RNA total de referência humano (Agilent, EUA) foi utilizado e, para a normalização, o RNU48 foi utilizado como um gene de referência. O miR-371a-3p discriminou tecidos tumorais de tecidos controlo com alta sensibilidade e especificidade (AUC = 0,99). Além disso, os seminomas apresentaram níveis mais elevados de expressão do miR-371a-3p em comparação com amostras de TGCT não-seminomatoso, revelando também diferenças significativas entre eles. Contudo, os TGCTs pré-púberes apresentaram níveis mais baixos de expressão do miR-371a-3p do que TGCTs pós-púberes. Globalmente, os níveis de expressão do miR-371a-3p diminuíram em paralelo com a diferenciação celular progressiva. Concluímos que o miR-371a-3p é específico para TGCT e pode ser clinicamente útil para a deteção precoce e monitorização desta doença oncológica.Testicular germ cell tumors (TGCT) are heterogeneous group of neoplasms, mostly affecting young men. Curability rates are high and adequate treatment relies in careful and accurate pathological and clinical assessment. Indeed, TGCT histopathological subtyping is critical for adequate therapeutic decision. Considering limitation of currently available serum biomarkers, novel candidates have been proposed, most notably miR-371a-3p, which outperformed classical serum markers, but no detailed information concerning TGCT subtype was available. Thus, we carried out evaluation of miR-371a-3p expression levels among TGCT subtypes using a consecutive cohort of tissue samples. After RNA isolation and cDNA synthesis, miR-371a-3p expression levels were measured in 154 tissue samples of TGCT and in 15 non-tumoral tissues by real-time quantitative PCR (RT-qPCR). To allowed generation of a standard curve for relative quantification and ascertain PCR efficiency cDNA from total Human Reference RNA (Agilent, USA) was used and for normalization RNU48 was used as a reference gene. MiR-371a-3p discriminated TGCT from control tissues with high sensitivity and specificity (AUC=0.99). Furthermore, seminomas displayed higher miR-371a-3p expression levels compared to nonseminomatous TGCT, which also disclosed significant differences among them. Nonetheless, prepubertal TGCT depicted lower miR-371a-3p expression levels than postpubertal TGCT. Globally, miR-371a-3p expression levels decreased in parallel with progressive cell differentiation. We concluded that miR-371a-3p is TGCT-specific and it might be clinically useful for early detection and disease monitoring.
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Costa, Ana Laura da Silva. "DNA Methylation Profiling as a Tool for Testicular Germ Cell Tumors Subtyping." Master's thesis, 2017. https://repositorio-aberto.up.pt/handle/10216/109407.
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Guimarães, Rita Manuela Marques Castro. "The role of DNA modifying enzymes in malignant testicular germ cell tumors." Master's thesis, 2019. https://hdl.handle.net/10216/124853.
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Guimarães, Rita Manuela Marques Castro. "The role of DNA modifying enzymes in malignant testicular germ cell tumors." Dissertação, 2019. https://hdl.handle.net/10216/124853.
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Costa, Ana Laura da Silva. "DNA Methylation Profiling as a Tool for Testicular Germ Cell Tumors Subtyping." Dissertação, 2017. https://repositorio-aberto.up.pt/handle/10216/109407.
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"The role of DNA methylation in the regulation and action of microRNA in testicular germ cell tumor." 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1290659.
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It was previously demonstrated that miR-199a was down-regulated in testicular germ cell tumor (TGCT) partly caused by hypermethylation of its promoter. More detailed analyses showed that miR-199a-5p, one of its two derivatives, suppressed TGCT invasiveness and proliferation via directing targeting PODXL and MAFB. The biological role of the other derivative, miR-199a-3p in TGCT, remains largely uncharacterized. In this project we identified DNMT3A, the de novo methyltransferase, as a direct target of miR-199a-3p using a 3’-UTR reporter assay. In NT2 (NTera 2) and HT (Hs 1.Tes) cells, miR-199a-3p regulated the expression of endogenous DNMT3A (both DNMT3A1 and DNMT3A2 isoforms), especially DNMT3A2 isoform. In clinical samples, the expression of DNMT3A2 and miR-199a-3p were reciprocally regulated. However, DNMT3A did not regulate miR-199a expression. Further characterization of miR-199a-3p revealed that it negatively regulated DNA methylation partly through targeting DNMT3A. MiR-199a-3p could restore the expression of APC and MGMT via de-methylation in their promoters. Our studies demonstrated the dysregulation of miR-199a-3p in TGCT may provide novel mechanistic insights into TGCT carcinogenesis and suggested a potential therapeutic use of synthetic miR-199a-3p oligonucleotides as effective demethylation agent in the treatment of TGCT. However, since DNMT3A expression did not regulate miR-199a expression, the mechanism of promoter DNA hypermethylation of miR-199a in TGCT needs further investigation.MiR-199a is encoded by two loci in the human genome, namely, miR-199a-1 on chromosome 19 and miR-199a-2 on chromosome 1. Another microRNA, miR-214, also locates on chromosome 1. Previous study revealed that it is co-transcribed with miR-199a-2, which is directed by miR-199a-2 promoter. However, the biological significance of the co-expression of miR-199a and miR-214 remains largely unknown. In this project, it was determined that miR-199a and miR-214 were concordantly expressed in TGCT. Silencing of DNMT1 increased the expression of miR-199a and miR-214, accompanied by de-methylation in the promoters of miR-199a-1/2. Overexpression of TP53 down-regulated the expression of DNMT1 and increased the expression of mature miR-199-3p/5p and miR-214. In addition, silencing of PSMD10 up-regulated the expression of TP53, while miR-214 over-expression resulted in PSMD10 down-regulation and TP53 up-regulation. Collectively, our findings highlighted a miR-199a/miR-214/PSMD10/TP53/DNMT1 self-regulatory network, which caused the down-regulation of miR-199a, miR-214 and TP53, as well as the up-regulation of DNMT1 and PSMD10 in TGCT. These observations partly explain the mechanism of promoter DNA hypermethylation in miR-199a in TGCT. They also suggest a potential therapeutic approach by targeting the miR-199a/miR-214/PSMD10/TP53/DNMT1 regulatory network in the treatment of TGCT.
先前的研究證實miR-199a在睾丸生殖細胞腫瘤 (簡稱睾丸癌) 中是低表達的，部分歸因於其啟動子區域過度甲基化。對其功能研究發現miR-199a能抑制睾丸癌細胞的生長，侵襲和轉移，且miR-199a的抑癌屬性應歸功於它的兩個衍生物之一miR-199a-5p。然而，miR-199a的另一個衍生物miR-199a-3p在睾丸癌中的生物學功能仍然在很大程度上是未知的。此研究中，DNMT3A被鑒定為miR-199a-3p的直接靶定目標。在NT2和HT細胞中，miR-199a-3p能調控內源性DNMT3A(DNMT3A1和DNMT3A2)的表達水準，尤其是DNMT3A2。在臨床樣本中，DNMT3A2的表達水準與miR-199a-3p的表達水準呈負相關。但DNMT3A並不能調控miR-199a的表達水準。進一步研究顯示過表達miR-199a-3p能減少APC和MGMT啟動子區域甲基化而恢復其表達水準。研究證實異常表達的miR-199-3p可能在睾丸癌的癌變過程中發揮作用，並提出一個潛在的治療方案，即使用miR-199a -3p作為有效的去甲基化藥劑治療睾丸癌。然而睾丸癌中導致miR-199a啟動子區域過度甲基化的機制有待進一步研究。
在人類基因組中，miR-199a-1(位於19號染色體)和miR-199a-2(位於1號染色體)都編碼miR-199a。同時miR -214也位於1號染色體，研究表明miR-214與miR-199a-2由miR-199a-2啟動子介導共同轉錄，但miR-199a和miR- 214共同表達的生物學意義仍未知。此研究中，miR-199a和miR-214在睾丸癌中的表達呈現一致性。沉默DNMT1後miR-199a和miR-214的表達水準顯著提高，並伴隨著miR-199a-1/2啟動子區域的DNA去甲基化。在NT2細胞中。過表達TP53能下調DNMT1的表達水準，同時上調miR-199-3p/5p和miR- 214的表達水準。此外，過表達miR -214能導致PSMD10表達水準的下調以及TP53表達水準的上調。綜上所述，我們提出一個miR-199a/miR-214/PSMD10/TP53/DNMT1自我調控網路，此調控通路能引起睾丸癌中miR-199a，miR-214和TP53表達水準的下調，以及DNMT1和PSMD10表達水準的上調，且部分解釋睾丸癌中miR-199a啟動子區域過度甲基化的機制，同時該調控網路可作為治療睾丸癌的一個潛在靶點。
Chen, Bifeng.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2014.
Includes bibliographical references (leaves 103-127).
Abstracts also in Chinese.
Title from PDF title page (viewed on 20, December, 2016).
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
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Lobo, João Pedro da Silva Machado. "Uncovering novel prognostic and predictive epigenetic biomarkers in malignant testicular germ cell tumors." Doctoral thesis, 2021. https://hdl.handle.net/10216/136707.
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Lin, Choa Yi, and 林肇怡. "Role of IGF-1R-mediated signaling in regulation of pluripotent human testicular germ cell tumors." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/89078122565852102465.
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碩士臺北醫學大學
醫學科學研究所
97
Recent studies demonstrated that the IGF-1R signaling might promote the cell proliferation, survival, and drive cells undergoing EMT transition to be malignant tumors. Oct-4 protein is known as transcription factor specifically displayed in embryonic stem cells (ES cells) and germline stem cells. In human germ cell tumors, Oct-4 is overexpressed in seminomas and embryonal carcinomas (ECs). Further clinical evidence suggested that human seminoma and ECs also highly express growth factors IGF-I and IGF-II. This result is similar to that of hES cells which depend on the IGF-1R signaling to maintain their self-renew and pluripotency. Our previous studies indicated that the pluripotency of mouse germline stem cells was maintained by the IGF-I dependent pathway (2009, The FASEB J). To further identify the role of IGF-I/ IGF-1R signaling in pluripotent germ cell tumors, we used NT2 and NCCIT cells as model to examine the effect of IGF-I/ IGF-II/ IGF-IR signaling on the germ cell pluripotency. In our study, by utilizing both real-time PCR and Western blotting, we observed the up-regulation of pluripotent Oct-4 protein in NT2 and NCCIT cells (the pluripotent germ cell tumors). Further study using PPP (a specific inhibitor for IGF-1R phosphorylation) to block the IGF-I/ IGF-1R signaling, the downregulation of Oct-4 as well as neuron-like differentiation of NT2 cell were demonstrated. Exogeneous addition of IGF-I and /or IGF-II in medium significantly increased the Oct-4 expression level in NT2 cells. Furthermore, down-regulation of IGF-1R expression by shRNA siginificantly suppressed the IGF-1R as well as the Oct-4 expression in NT2, but not in NCCIT cells. Together with these observations strongly suggested the maintenance of germ cell pluripotency and tumorigenesis by IGF-I/ IGF-1R-mediated signals. In summary, here we presented the regulation of IGF-I/ IGF-1R signaling in pluripotent germ cell tumors. This finding may contribute to important clinical therapeutic targeting for cancer treatment.