Thematische Bibliographien / Bcl-2 Receptors

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Auswahl der wissenschaftlichen Literatur zum Thema „Bcl-2 Receptors“

Autor: Grafiati

Veröffentlicht am 4. Juni 2021

Zuletzt aktualisiert am 1. Februar 2022

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Zeitschriftenartikel zum Thema "Bcl-2 Receptors"

Rodewald, Hans-Reimer, Claudia Waskow und Corinne Haller. „Essential Requirement for C-KIT and Common γ Chain in Thymocyte Development Cannot Be Overruled by Enforced Expression of Bcl-2“. Journal of Experimental Medicine 193, Nr. 12 (18.06.2001): 1431–38. http://dx.doi.org/10.1084/jem.193.12.1431.

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The thymus in mice lacking both the receptor tyrosine kinase c-kit and the common cytokine receptor γ chain (γc) is alymphoid because these receptors provide essential signals at the earliest stages of thymocyte development. The signals transduced by these receptors potentially regulate proliferation, survival, or differentiation, but the contribution of each receptor to distinct intracellular signaling cascades is only poorly defined. Here, we have examined whether enforced expression of Bcl-2 can rescue thymocyte development in c-kit and γc single or double mutant mice. A bcl-2 transgene (Eμ-bcl-2-25; expressed in the T cell lineage) was introduced into (a) c-kit and γc wild-type (c-kit+γc+bcl+), (b) c-kit–deficient (c-kit−γc+bcl+), (c) γc-deficient (c-kit+γc−bcl+), or (d) c-kit and γc double-deficient mice (c-kit−γc−bcl+). The bcl-2 transgene was functionally active in wild-type and c-kit or γc single mutants, as it promoted survival of ex vivo isolated thymocytes, including pro-T cells. In vivo, however, transgenic Bcl-2 did not release T cell precursors from their phenotypic block and failed to increase progenitor or total thymocyte cellularity in c-kit or γc single or double mutants. These data argue strongly against a role for Bcl-2 as a key mediator in signaling pathways linked to cytokine and growth factor receptors driving early thymocyte development.

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Vervliet, T., E. Decrock, J. Molgo, V. Sorrentino, L. Missiaen, L. Leybaert, H. De Smedt, N. N. Kasri, J. B. Parys und G. Bultynck. „Bcl-2 binds to and inhibits ryanodine receptors“. Journal of Cell Science 127, Nr. 12 (24.04.2014): 2782–92. http://dx.doi.org/10.1242/jcs.150011.

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Ibeas, Patricia, Ana Lopez-Gonzalez, Bernard Gaston Doger de Speville, Miriam Huelves, Roberto Lopez, Elena Almagro, Magda Palka, Andrea Ruiz-Valdepeñas, David Perez Callejo und Mariano Provencio. „Prognostic value of Bcl-2 in breast cancer.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): e11527-e11527. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e11527.

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e11527 Background: Breast cancer is a heterogeneous disease with prognostic factors used by the oncologists to decide the treatment. Bcl2 is an antiapoptotic proto-oncogen involved in DNA break process that has been defined historically as a poor prognostic factor. This study was conducted to confirm whether or not bcl-2 is an independent prognostic factor. Methods: In this study, we have reviewed all patients who were diagnosed at our hospital between January 2007 and December 2008 (99 patients). Inclusion criteria were patients diagnosed of breast cancer whose anatomopathological report showed bcl-2 status as well as the rest of the parameters measured. The parameters measured were age, past medical history, menopausal status, TNM, hormone receptors, HER2, p53, Ki67, bcl-2, treatment applied, date of relapse (if any), date of death ( if occurred). All of them characterized by centralization measures. We conducted an analysis of prognostic factor that influenced survival. Results: The average age of diagnosis is 54.6 years (30-94 years). 42.4% were premenopausal. The average tumor size was 2.59 cm ( 0.5-7.5 cm). 81.8% had positive estrogen receptors. 92% were HER2 negative by inmunohistochemistry. 62.6% were p53 negative. Bcl-2 was 84.8% positive. The distribution by stage at diagnosis was: stage I 26.3%; stage II 49.5%; stage III 22.2%. Disease free survival for patients bcl2(+) was 45.6 months versus 22.6 months for patients bcl2 (-) (0.12-22.2; p: 0.00125). Overall survival for the group bcl2(+) was 48 months (41.6-54.3) and bcl2 (-) was 48.24 months (42.48 to 54). Conclusions: We can state that bcl2 is not an independent prognostic factor. Despite the value in other diseases, the determination of bcl-2 by inmunohistochemistry in breast cancer in stages I, II and III at the moment of the diagnosis does not provide any prognostic information.

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Ueno, Hiroo, Eisaku Kondo, Ritsuko Yamamoto-Honda, Kazuyuki Tobe, Tetsuya Nakamoto, Ko Sasaki, Kinuko Mitani et al. „Association of Insulin Receptor Substrate Proteins with Bcl-2 and Their Effects on Its Phosphorylation and Antiapoptotic Function“. Molecular Biology of the Cell 11, Nr. 2 (Februar 2000): 735–46. http://dx.doi.org/10.1091/mbc.11.2.735.

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Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.

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Yin, Xiaobei, Ting He, Rui Chen, Hui Cui und Genlin Li. „Impact of neurotrophic factors combination therapy on retinitis pigmentosa“. Journal of International Medical Research 48, Nr. 11 (November 2020): 030006052096783. http://dx.doi.org/10.1177/0300060520967833.

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Objective We aimed to determine the location of neurotrophic receptors tropomyosin receptor kinase (Trk)B, TrkC, and ciliary neurotrophic factor receptor (CNTFR)α in the retina of retinal degeneration ( rd) mice and to explore the dynamic changes of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X-protein (Bax), and microtubule-associated protein light chain 3 (LC3) expression and ultrastructure in the retina of rd mice intravitreally injected with neurotrophic factors. Methods Rd mice aged 2 and 3 weeks post-natally (PN) received intravitreal injections of neurotrophic factors. Two weeks later, their retinas were harvested for the detection of Bax, Bcl-2, and LC3 mRNA and protein expression. Results TrkB and TrkC expression levels were lower at 3 weeks PN compared with 0, 1, and 2 weeks PN, but CNTFRα expression was still detected in certain layers. The three receptors were expressed in different retinal layers at the same timepoint. Bax expression was downregulated in, rhBDNF + rhCNTF, rhBDNF + rhNT-3, groups 2 weeks after intravitreal injection; Bcl-2 expression was upregulated in the rhBDNF + rhCNTF + rhNT-3 group at PN-4w; and LC3 expression was upregulated in rhBDNF + rhCNTF + rhNT-3 groups. Conclusions The combined use of neurotrophic factors had a more significant effect on Bax, Bcl-2, and LC3 expression than the same factors used alone.

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Silvestrini, R., E. Benini, S. Veneroni, M. G. Daidone, G. Tomasic, P. Squicciarini und B. Salvadori. „p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients.“ Journal of Clinical Oncology 14, Nr. 5 (Mai 1996): 1604–10. http://dx.doi.org/10.1200/jco.1996.14.5.1604.

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BACKGROUND AND PURPOSE The tumor-suppressor gene TP53 and the proto-oncogene bcl-2 encode, respectively, for a nuclear phosphoprotein and for a mitochondrial protein involved in multiple cellular functions. The proteins provide prognostic information in node-negative breast cancer and are supposed to influence treatment responsiveness. We analyzed the predictive role of p53 and bcl-2 expression, alone and in association with other variables, in postmenopausal women with node-positive, estrogen receptor-positive (ER+) breast cancers treated with radical or conservative surgery plus radiotherapy and adjuvant tamoxifen for at least 1 year. PATIENTS AND METHODS On 240 resectable cancers, we determined the expression of p53 and bcl-2, using immunohistochemistry, cell proliferation (3H-thymidine labeling index [3H-dT LI]), and ER and progesterone receptors (PgR). RESULTS p53 expression and 3H-dT LI were weakly related to one another and both were unrelated to bcl-2. Relapse-free and distant metastasis-free survival at 5 years were significantly lower for patients with tumors that highly expressed p53 (P = .0001) and for those that weakly expressed or did not express bcl-2 (P = .02). However, p53, but not bcl-2, provided prognostic information independent of tumor size, axillary node involvement, steroid receptors, and 3H-dT LI. Moreover, the simultaneous p53 overexpression and lack of PgR identified patients at maximum risk of relapse, whereas bcl-2 overexpression, associated with a low 3H-dT LI or the presence of PgR, improved the prognostic resolution for low-risk patients. CONCLUSION p53 expression appears to be indicative of clinical outcome in postmenopausal patients treated with tamoxifen. Whether p53 overexpression and weak bcl-2 expression are indicators of biologic aggressiveness, regardless of treatment, or of hormone resistance remains to be defined.

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Mutiah, Roihatul, Muhammad Fawaz Hariz, Yen Yen Ari Indrawijaya und Burhan Ma'arif. „In Silico Prediction of Isoliquiritigenin and Oxyresveratrol Compounds to BCL-2 dan VEGF-2 Receptors“. Indonesian Journal of Cancer Chemoprevention 10, Nr. 2 (09.07.2019): 51. http://dx.doi.org/10.14499/indonesianjcanchemoprev10iss2pp51-59.

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Isoliquiritigenin and oxyresveratrol are compounds that have been reported to have anticancer activities. This study aimed to predict cytotoxic activity, toxicity and physicochemical properties of the compounds isoliquiritigenin and oxyresveratrol. Prediction of physicochemical properties referred to Lipinski rules of five using the pkCSM online tool. Prediction of compounds toxicity using Protox II online tool while ligand interaction with receptors using Molegro Virtual Docker (MVD). Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) (PDB: 2RL5) and B Cell Lymphoma BCL-2 (PDB: 4AQ3) were used as target cancer receptor proteins. In silico predictive results showed that oxyresveratrol and isoliquiritigenin complied with Lipinski rules of five, predictive values of LD50 between 500-2000 mg/kg respectively 1560 mg/kg and 1048 mg/kg. The docking result was in the form of bound energy described by Rerank Score (RS). A compound having a small RS value was predicted to have greater activity. RS of oxyresveratrol on 2RL5: -73.0413 and 4AQ3: -87.9985, while isoliquiritigenin on 2RL5: -68.0282 and 4AQ3: -78.5041. The cytotoxic activity of oxyresveratrol was also shown by hydrogen bonds in active amino acids (2RL5: Cys 919 in 4AQ3: Tyr 67). From docking results of both compounds, oxyreveratrol had greater activity than isoliquiritigenin to both target cancer receptor proteins and complied Lipinski rules of five and have a low toxicity.Keywords: cytotoxicity, toxicity, isoliquiritigenin, oxyresveratrol, in silico.

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Das, Samarjit, Gerald A. Cordis, Nilanjana Maulik und Dipak K. Das. „Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation“. American Journal of Physiology-Heart and Circulatory Physiology 288, Nr. 1 (Januar 2005): H328—H335. http://dx.doi.org/10.1152/ajpheart.00453.2004.

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Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 μM resveratrol; 3) 10 μM resveratrol + 1 μM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A1 receptor blocker); 4) 10 μM resveratrol + 1 μM 8-(3-chlorostyryl)caffeine (CSC; adenosine A2a receptor blocker); 5) 10 μM resveratrol + 1 μM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A3 receptor blocker); or 6) 10 μM resveratrol + 3 μM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A1 and A3 receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A1 and A3 receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.

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McCullers, Deanna L., und James P. Herman. „Mineralocorticoid receptors regulate bcl-2 and p53 mRNA expression in hippocampus“. NeuroReport 9, Nr. 13 (September 1998): 3085–89. http://dx.doi.org/10.1097/00001756-199809140-00031.

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Banta, Karl L., Xinyue Wang, Phani Das und Astar Winoto. „B cell lymphoma 2 (Bcl-2) residues essential for Bcl-2's apoptosis-inducing interaction with Nur77/Nor-1 orphan steroid receptors“. Journal of Biological Chemistry 293, Nr. 13 (02.02.2018): 4724–34. http://dx.doi.org/10.1074/jbc.ra117.001101.

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Dissertationen zum Thema "Bcl-2 Receptors"

Witcher, Michael. „Interaction of the anti-apoptotic protein BAG-1 with the vitamin D receptor“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0010/MQ52698.pdf.

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Pinheiro, Anderson 1981. „Receptores de estrógeno e progesterona, Ki67, Bcl-2 E Cox-2 em pólipos endometriais de mulheres na pré e pós-menopausa e associação com a obesidade, : Estrogen and progesterone receptors, Ki67, Bcl-2 and Cox-2 markers in benign endometrial polyps in pre and postmenopausal women and their association with obesity“. [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310480.

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Orientador: Lúcia Helena Simões da Costa Paiva
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-11-07T13:42:39Z (GMT). No. of bitstreams: 1 Pinheiro_Anderson_M.pdf: 3122120 bytes, checksum: dced5efa50ee11a7d5554366020908bb (MD5) Previous issue date: 2012
Resumo: Introdução: A prevalência de obesidade tem aumentado em todo o mundo e hoje já representa um problema de saúde pública. Na população feminina, seu aumento ocorre principalmente nos anos próximos da transição para menopausa. O aumento de peso representa um risco para diversas comorbidades, dentre elas um importante fator de risco para patologia endometrial. A etiologia e a patogênese dos pólipos não estão completamente esclarecidas. Estuda-se se o desenvolvimento dos pólipos endometriais está diretamente relacionado à presença de receptores hormonais, além de estar relacionado a mecanismos envolvidos à proliferação e à apoptose celular. Objetivos: Avaliar a imunoexpressão dos receptores de estrógeno (RE), progesterona (RP), Cox-2, Ki67 e Bcl-2 em pólipos endometriais benignos na pré e pós-menopausa e associação com a obesidade. Materiais e métodos: Dentre 1050 mulheres submetidas à histeroscopia cirúrgica no Hospital da Mulher Prof. Dr. Aristodemo Pinotti - CAISM/UNICAMP, de janeiro de 1998 a dezembro de 2008, 800 foram casos de polipectomia endometrial confirmados com exame anatomopatológico. Deste total, foram excluídas as usuárias de Tamoxifeno, as que faziam uso de terapia hormonal e os casos de pólipos malignos ou pré-malignos. Obteve-se uma amostra de 515 pólipos endometriais benignos em mulheres na pré e pós-menopausa. Foram avaliadas as expressões de RE, RP, Bcl-2, Ki67 e Cox-2, através de imuno-histoquímica, segundo a porcentagem de células coradas, intensidade da coloração e escore final. Os escores finais de RE, RP, Bcl-2, Cox-2 variam de 0 a 8 e o de Ki67 de 0 a 3. A mediana dos escores finais de RE, RP, Bcl-2, Cox-2 e Ki67 no epitélio glandular e no estroma dos pólipos foi comparada entre mulheres obesas e não obesas na pré e pós-menopausa, utilizando os testes qui-quadrado, exato de Fisher ou não paramétrico de Mann-Whitney. Resultados: A mediana do escore final de receptores hormonais mostrou maior expressão de RP no estroma e no epitélio glandular das mulheres obesas na pós-menopausa, sem diferença em relação à expressão dos RE. Em mulheres na pré-menopausa não houve diferença na expressão de RE e RP entre obesas e não obesas. Nos pólipos endometriais de mulheres pós-menopausadas houve maior expressão de Cox-2 e Bcl-2 no epitélio glandular das mulheres obesas do que em relação às mulheres não obesas. Não houve diferenças em relação ao estroma endometrial. Na pré-menopausa, houve maior expressão de Bcl-2 apenas no epitélio glandular das mulheres obesas. Não houve diferenças na expressão de Ki67 entre obesas e não obesas tanto na pós-menopausa quanto na pré-menopausa. Conclusões: Os pólipos de mulheres obesas apresentam, na pós-menopausa, maior expressão de RP glandular e estromal, Cox-2 glandular e Bcl-2 glandular, sem diferenças na expressão de Ki67. Estes dados sugerem que sua etiopatogênese dos pólipos em obesas parece estar mais relacionada aos receptores de progesterona, à inibição da apoptose e aos mecanismos relacionados à inflamação celular
Abstract: Introduction: The prevalence of obesity has increased worldwide and represents a public health problem nowadays. The female population, considerably presents its increase in the coming years of the transition to menopause. Weight gaining represents a risk for various comorbidities, but among them all, it is an important risk factor for the endometrial pathology. The polyps etiology and pathogenesis have not been completely clarified so far. It has been studied whether the endometrial polyps development is directly related to the presence of hormone receptors, besides being associated with mechanisms involved in the proliferation and cellular apoptosis.Objectives: To evaluate the immunoexpression of estrogen and progesterone receptors, Ki67, Bcl-2 and Cox-2 in benign endometrial polyps in pre and postmenopausal women and their association with obesity. Methods: It was observed that among 1050 women who underwent hysteroscopic surgery at the "Prof. Dr. José Aristodemo Pinotti" Women's Hospital-CAISM-UNICAMP from January 1998 to December 2008, 800 were confirmed with endometrial polyp anatomopathological diagnosis. Of this total amount, it was excluded tamoxifen users, those who used hormone therapy and cases of malignant or pre-malignant polyps. It was obtained a sample of 515 benign endometrial polyps in women before and after menopause. It was also assessed the expression of ER, PR, Bcl-2, COX-2 and Ki67 through immunohistochemistry according to stained cells percentage, staining intensity, and the final score. The ER, PR, Bcl-2, Cox-2 final score ranges from 0 to 8 and the Ki67 from 0 to 3). The ER, PR, Bcl-2, Cox-2 and Ki67 median final scores in the glandular epithelium and stroma of the polyps were compared among obese and nonobese women, in pre and postmenopausal condition, using the Chi-square Fisher's exact test or nonparametric Mann-Whitney test. Results: The hormonal receptors median final score has showed an increased expression of progesterone receptors in the stroma and glandular epithelium of postmenopausal obese women but there was no difference in expression of ER estrogen receptors. In premenopausal women, there was no difference in expression of ER and PR among obese and nonobese women. The endometrial polyps in postmenopausal women have showed a higher expression of Cox-2 and Bcl-2 in glandular epithelium in obese women rather than in nonobese women. There were no differences in the endometrial stroma. In premenopausal women, there was a higher expression of Bcl-2 only in the obese women glandular epithelium. There were no differences in Ki67 expression among obese and nonobese both postmenopausal and premenopausal women. Conclusions: Obese women polyps, in postmenopausal condition, have increased expression of glandular and stromal PR, Cox-2 and Bcl-2 glandular. However, there are no differences in the Ki67 expression . These data suggest that its etiopathogenesis in obese women polyps, seem to be related to progesterone receptors, apoptosis inhibition and also to mechanisms associated with cellular inflammation
Mestrado
Fisiopatologia Ginecológica
Mestre em Ciências da Saúde

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Nougarede, Adrien. „Molecular basis of BCL2L10/Nrh oncogenic activity in breast cancer“. Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1192/document.

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L'apoptose, ou « mort cellulaire programmée », joue un rôle clé dans de nombreux processus biologiques. Les protéines de la famille Bcl-2, dont l'expression est souvent altérée dans les cellules tumorales, sont les principaux régulateurs de l'apoptose. Parmi cette famille, la fonction exacte du répresseur apoptotique Nrh, aussi appelé BCL2L10 ou Bcl-B, reste à ce jour mal comprise. Bien que son expression ne soit pas détectable dans la plupart des tissus sains, on retrouve des niveaux élevés de Nrh corrélés à un mauvais pronostique dans les cancers du sein et de la prostate. Nous avons mis au jour un nouveau mécanisme selon lequel Nrz, l'orthologue de Nrh chez le poisson zèbre, interagit avec le domaine de liaison du ligand IP3 du canal calcique IP3R1. Il s'est avéré que la régulation négative des flux calciques par Nrz est critique lors du développement embryonnaire du poisson zèbre. Grâce à ces nouvelles données, nous avons cherché à comprendre la fonction de Nrh chez l'Homme, dans un contexte pathologique. Nous avons montré que Nrh interagit via son domaine BH4 avec le domaine de liaison du ligand du récepteur IP3R1 humain pour réguler l'homéostasie calcique et la mort cellulaire. Cette interaction définit Nrh comme la seule protéine de la famille Bcl-2 à réguler négativement la mort cellulaire exclusivement au niveau du réticulum endoplasmique. Pour aller plus loin, nous avons montré que la dissociation du complexe Nrh/IP3Rs sensibilise des cellules tumorales mammaires à l'action d'agents chimiothérapeutiques. Pour finir, nos résultats apportent une explication moléculaire sur la contribution de Nrh dans la résistance aux thérapies anti-tumorales
Apoptosis, also called “Programmed Cell Death”, plays a key role in many biological processes and pathologies. The B-cell lymphoma 2 (Bcl-2) proteins, whose expression is often altered in tumor cells, are the main regulators of apoptosis.Among this family, the actual physiological function of the human apoptosis inhibitor Nrh, also referred to as BCL2L10 or Bcl-B, remains elusive. Although in most healthy tissues the Nrh protein is nearly undetectable, clinical studies have shown that Nrh expression is correlated with poor prognosis in breast and prostate carcinomas. We have shed light on a novel mechanism by which Nrz, the zebrafish ortholog of Nrh, was found to interact with the Ligand Binding Domain (LBD) of the Inositol-1,4,5-triphosphate receptor (IP3R) type-I Ca2+ channel. Indeed, the regulation of IP3Rs-mediated Ca2+ signaling by Nrz was shown to be critical during zebrafish embryogenesis. We used the knowledge gained with the zebrafish model to investigate Nrh function in cancer. We showed that Nrh interacts with the LBD of IP3Rs via its BH4 (Bcl-2 Homology 4) domain, which is critical to regulate intracellular Ca2+ trafficking and cell death. Actually, this interaction seems to be unique among the Bcl-2 family, and sets Nrh as the only Bcl-2 homolog to negatively regulate apoptosis by acting exclusively at the Endoplasmic Reticulum. Furthermore, we showed that disruption of the Nrh/IP3Rs complex primes Nrh-dependent cells to apoptotic cell death and enhances chemotherapy efficiency in breast cancer cell lines.Lastly our results bring a new insight to the role of Nrh regarding chemotherapy resistance

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Al, Dulaimi Dina. „Développement et fonction des cellules INKT“. Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC116.

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Les cellules invariantes « natural killer » T (iNKT) constituent une population particulière de LT non conventionnelle qui exprime un récepteur TCRαβ semi-invariant composé de la chaine Vα14-Jα18 associée aux chaines Vβ8, -7 ou -2 chez la souris et dont le développement a lieu dans le thymus. Ainsi, les cellules iNKT sont capables de reconnaitre via leur TCR des antigènes de type glycolipidique présentés par une molécule de classe I non polymorphique : le CD1d. Ces cellules sont connues pour être impliquées dans diverses réponses immunes grâce à leur capacité à produire rapidement des cytokines immunorégulatrices. De la même façon que les LTc SP CD4+, il existe trois phénotypes de cellules iNKT : Th1, -2 et -17 permettant de distinguer trois sous-populations de cellules iNKT. La sous-population iNKT1 dite iNKT conventionnelle exprime des récepteurs appartenant au lignage NK. Cette sous-population est localisée préférentiellement dans le foie, le thymus et la rate et produit majoritairement de l’IFN-. La sous-population iNKT2, qui reste jusqu’à aujourd’hui insuffisamment décrite, se localise préférentiellement dans les poumons et produit majoritairement de l’IL-4 et de l’IL-13. La sous-population iNKT17 a été caractérisée et mise en évidence au sein de notre laboratoire comme une sous-population de cellules iNKT exprimant le facteur de transcription RORt et capable de sécréter de l’IL-17 en réponse à l’IL-1 et l’IL-23 et se localisant principalement dans les ganglions périphériques et la peau. A ce jour, seul le développement des cellules iNKT conventionnelles est bien connu tandis que celui des cellules iNKT17 demeurent ignorés. Ainsi, ayant remarqué une faible proportion des cellules iNKT17 dans le thymus de la souris C57BL/6 comparées aux autres sous-populations de cellules iNKT, nous nous sommes intéressés dans un premier temps à expliquer les causes de cette faible distribution de cette sous-population, ainsi qu’à définir la séquence d’acquisition de ses marqueurs lors de son développement thymique et de sa migration en périphérie. Les résultats montrent que ces cellules n’ont aucun défaut de prolifération, ni de réponse aux cytokines de l’homéostasie permettant d’expliquer leur plus faible nombre. En revanche, nous avons constaté une absence d’accumulation thymique de ces cellules qui ont la capacité de migrer en périphérie, accompagnée d’une sensibilité plus accrue à la mort par apoptose et une diminution de l’expression des facteurs de survie comme le Bcl-2 pouvant ainsi expliquer leur nombre réduit. Les analyses de leur développement aux stades précoces ont montré un biais préétabli de leur faible nombre observable dès le stade CD44-. L’étude de leur ontogénique a permis de montrer une cinétique d’acquisition séquentielle des marqueurs CCR6 et CD138 permettant d’établir pour la première fois un modèle de maturation thymique de cette sous-population iNKT17 qui était encore inconnue. Ainsi, au stade précoce HSAhigh, les cellules iNKT RORt+ observé correspondent à des précurseurs communs des cellules iNKT et non pas à des précurseurs des cellules iNKT17 montrant que la différenciation de ces cellules ne se fait pas au stade de sélection positive et que leur faible nombre dépend des signaux que ces cellules reçoivent lors de leur engagement vers le lignage “Th17 like“
Invariant natural killer cells T (iNKT) constitute a particular population of unconventional LT which expresses a semi-invariant TCRαβ receptor composed of the Vα14-Jα18 chain associated with the Vβ8, -7 or -2 chains in mice and which develops in the thymus. Thus, iNKT cells are able to recognize glycolipid antigens via their TCR presented by a non-polymorphic class I molecule: CD1d. These cells are known to be involved in various immune responses because of their ability to rapidly produce cytokines. However, like conventional SP T CD4+ lymphocytes, iNKT cells can differentiate into three phenotypes: Th1, -2 and -17. The iNKT1 subset also named conventional iNKT cells expresses receptors belonging to the NK lineage, is mainly located in the liver, thymus and spleen and produces mainly IFN-. The iNKT2 subset which until now remains insufficiently described, is localized preferentially in the lungs and produces mainly IL-4 and IL-13. The iNKT17 subset has been characterized in our laboratory as a subset of iNKT cells expressing the RORt transcription factor and capable of secreting IL-17 in response to IL-1 and IL-23 and located mainly in the peripheral lymph nodes and the skin. To date, only the development of conventional iNKT cells is well known while that of iNKT17 cells remains unknown. Thus, having noticed the low distribution of the iNKT17 cells present in the thymus of the C57BL/6 mouse compared to other iNKT cell subset, we were initially interested in explaining the causes of this poor distribution of this subset, as well as to define the acquisition sequence of its markers during its thymic development and peripheral migration. The results show that these cells have no defect of proliferation or response to cytokines of homeostasis that can explain their lower number in the thymus. In contrast, we found a lack of thymic accumulation of these cells that have the ability to migrate peripherally, accompanied by increased sensitivity to death by apoptosis and decreased expression of survival factors such as Bcl-2 which can explain their reduced number. Analyzes of their development at early stages showed a pre-established bias of their low number from the CD44- stage. The study of their ontogeny has shown a sequential acquisition kinetics of CCR6 and CD138 markers to establish for the first time a model of thymic maturation of this iNKT subset which was still unknown

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Karlsson, Hannah. „CD19-targeting CAR T Cells for Treatment of B Cell Malignancies : From Bench to Bedside“. Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-232638.

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Immunotherapy for cancer is a young research field progressing at high speed. The first chimera of an antibody and a signaling chain was designed by Zelig Eshhar and was later further developed to enhance existing T cell therapy by combining a single-chain fragment of an antibody with the CD3 zeta chain of the TCR complex. T cells expressing these chimeric antigen receptors (CARs) could recognize and specifically kill tumor cells. However the T cells, lacked in persistence and tumor rejection did not occur. Thus, the CAR constructs have been improved by providing the T cell with costimulatory signals promoting activation. The focus of this thesis has been to evaluate second and third generation αCD19-CAR T cells for the treatment of B cell leukemia and lymphoma. B cell tumors commonly upregulate anti-apoptotic proteins such as Bcl-2, which generates therapy resistance. In the first paper a second generation (2G) αCD19-CD28-CAR T cell was combined with the Bcl-2 family inhibitor ABT-737. ABT-737 sensitized tumor cells to CAR T cell therapy and may be an interesting clinical combination treatment. In paper II, the phenotype and function of a third generation (3G) αCD19-CD28-4-1BB-CAR T cell were evaluated. B cell-stimulated CAR T cells showed increased proliferation and an antigen-driven accumulation of CAR+ T cells. 3G CAR T cells had equal cytotoxic capacity, similar lineage, memory and exhaustion profile phenotype compared to 2G CARs. However, 3G CAR T cells proliferated better and had increased activation of intracellular signaling pathways compared to 2G CAR T cells. In paper III, αCD19-CD28-4-1BB-CAR T cells were used to stimulate immature dendritic cells leading to an upregulation of maturation markers on co-cultured dendritic cells. Hence, CAR T cells may not only directly kill the tumor cells, but may induce bystander immunity that indirectly aids tumor control. This thesis also include supplementary information about the development and implementation of protocols for GMP production of CAR T cell batches for a phase I/IIa clinical trial currently ongoing for patients with refractory B cell leukemia and lymphoma. So far, two patients have safely been treated on the lowest dose.

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Fernandes, Luiz Flávio Cordeiro. „Caracterização morfológica da endometriose ovariana“. Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-12012016-104822/.

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Introdução: De origem controversa e repercussões imprevisíveis, o acometimento ovariano pela endometriose é considerado importante marcador de extensão da doença, pois pode se associar a endometriose profunda. Inúmeras teorias etiopatogênicas tentam explicar a gênese da endometriose ovariana e, duas delas recentemente tem sido reativadas, como a da metaplasia celômica que justificaria o conceito atual de endometriose intra-ovariana profunda e a da menstruação retrógrada, que explica a origem tubárea dos endometriomas. Estima-se em 5% a 10% de câncer ovariano em lesões de endometriose de ovário; enquanto, a frequência total de transformação maligna foi estimada entre 0,3 a 2,5%. Objetivo: Avaliar as formas de apresentação da endometriose ovariana e possíveis associações com o quadro clínico, com outros locais de doença, com os marcadores de atividade proliferativa (Ki-67), com a expressão de alterações moleculares dos mecanismos apoptóticos consideradas importantes no processo de carcinogênese das lesões de endometriose (p53 e Bcl-2) e com os receptores de estrogênio (dependência hormonal). Métodos: Estudo de coorte retrospectivo exploratório, com 63 pacientes operadas entre 2002 a 2012, com diagnóstico de endometriose ovariana preenchendo os critérios de inclusão e exclusão. Os preparados histológicos foram reavaliados e reclassificados de acordo com o tipo histológico, com a forma de apresentação e com a presença de infiltração do parênquima ovariano, sendo divididas em endometriose ovariana peritoneal, cistica e intraparenquimatosa. Foram avaliados a expressão do Ki-67, do p53, do Bcl- 2 e dos receptores de estrogênio no epitélio e no estroma tecidual. As pacientes ainda foram avaliadas de acordo com os sintomas clínicos e locais concomitantes de doença. Resultados: A forma de apresentação da endometriose ovariana mais frequente foi a cística (72,2%), seguida pela intraparenquimatosa (22,2%) e pela forma peritoneal (5,6%). Todas podem apresentar componente infiltrativo. A endometriose ovariana infiltrativa esteve presente em 30,5% dos casos. Não se evidenciou associação entre sintomas, distribuição anatômica do doença e expressão dos marcadores com as diferentes formas de apresentação ou com a infiltração do parênquima adjacente. Conclusão: A endometriose ovariana apresenta três formas distintas de apresentação, cística, intraparenquimatosa e peritoneal. Todas podem apresentar componente infiltrativo. Apesar da clara diferenciação histológica, ainda se deve identificar o significado clínico destes achados
Introduction: Of controversial origin and unpredictable repercussions, ovarian endometriosis is an important marker of disease extensiveness, as it may be related to deep infiltrating endometriosis. Numerous theories try to explain its origin, but two of them have been recently reactivated, such as celomic metaplasia, which would justify the concept of deep ovarian endometriosis, and retrograde menstruation, which can explain the tubal origin of ovarian endometriosis. It is estimated 5% to 10% of ovarian cancer in ovarian endometriosis, but malignant transformation may occur in 0.3 to 2.5% of the cases. Objective: Identify the presenting forms of ovarian endometrisosis and its possible relations to clinical symptoms, to other sites of disease, to proliferative activity markers (Ki-67), to the molecular expression of apoptotic mechanisms, considered important to the process of malignant transformation (p53 and Bcl-2) and to estrogen receptors (hormonal dependency). Methods: This is a retrospective exploratory cohort study, done between 2002 and 2012, including 63 women with laparoscopic diagnosis of ovarian endometriosis which fullfilled inclusion and exclusion criteria. The histologic specimens were reanalysed and reclassified according to the histologic pattern, to its presenting form and to the presence of parenchyma infiltration. The expression of Ki-67, p53, Bcl-2 and estrogen receptors were evaluated in the tissue epithelium and stroma. Clinical symptoms and concomitant sites of disease were also evaluated. Results: The most frequent form of ovarian endometriosis was cystic (72.2%), followed by intra-parenchymatous (22.2%) and peritoneal (5.6%). All of them can be infiltrative. The prevalence of infiltrative ovarian endometriosis was 30.5%. No association were found between symptoms, anatomical distribution of disease, markers expression and the presenting forms of ovarian endometriosis as well as adjacent parenchymal infiltration. Conclusion: Ovarian endometriosis has three distinct presenting forms, cystic, intra-parenchymatous and peritoneal. All of them can be infiltrative. Even though there is a clear histologic differentiation, its clinical significance is still to be determined

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Oliveira, Gislane Lelis Vilela de. „Avaliação da expressão de genes e proteínas anti- e pró-apoptóticos em pacientes com diabetes mellitus tipo 1 e esclerose múltipla submetidos ao transplante autólogo de células-tronco hematopoéticas“. Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-24112008-090815/.

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O diabetes mellitus tipo 1 (DM-1) e a esclerose múltipla (EM) são doenças auto-imunes órgão-específicas, inflamatórias, mediadas por células T e B auto-reativas e caracterizadas pela destruição seletiva de células b pancreáticas produtoras de insulina e do sistema nervoso central, respectivamente. Acredita-se que a desregulação da expressão de genes reguladores da maquinaria apoptótica possa contribuir para o desenvolvimento da auto-imunidade, visto que algumas dessas moléculas participam nos processos de tolerância central e periférica de linfócitos auto-reativos. O objetivo deste projeto foi analisar a expressão de moléculas reguladoras das vias intrínseca, extrínseca e da Família de proteínas inibidoras da apoptose (IAP) em 33 indivíduos saudáveis, 15 pacientes com DM-1 e 18 com EM submetidos à terapia de imunossupressão em altas doses seguida do transplante autólogo de células-tronco hematopoéticas (IAD/TACTH). As células mononucleares (CMN) foram isoladas do sangue periférico dos controles e de pacientes nos períodos pré-mobilização (pré-mob), pré-condicionamento (pré-cond), D+180, D+360, D+540 e D+720 pós-transplante. As CMN foram utilizadas para extração de RNA, síntese de cDNA, quantificação da expressão por PCR em tempo real dos genes a1, bcl-2, bcl-w, bcl-xL, mcl-1, bad, bak, bax, bid, bik, bim, bok, noxa, fas, fasL, c-FLIPL, cIAP-1 e cIAP-2 e protéica de Bcl-2, Bcl-xL, Bak, Bim e c-FLIPL por western-blotting. Os resultados de expressão gênica foram representados por unidades relativas de expressão em medianas nas diferentes amostras. Os pacientes com DM-1 apresentaram diminuição da expressão dos genes anti-apoptóticos bcl-2 (mediana: 0,98; p=0,04), bcl-w (0,08; p=0,04), mcl-1 (1254; p=0,03) e cIAP-1 (1,24; p=0,003) nas CMN dos pacientes no período pré-mob em relação aos indivíduos saudáveis (medianas: bcl-2: 7,58; bcl-w: 0,52; mcl-1: 1659; cIAP-1: 14,5), enquanto a expressão de cIAP-2 (60,8; p=0,0005) estava aumentada em relação aos controles (23,3). Foi observada redução significativa na expressão dos genes pró-apoptóticos bad (0,002; p<0,0001), bax (0,01; p=0,002) e fasL (1,66; p=0,001) no período pré-mob comparada aos controles sadios (bad: 0,23; bax: 2,79; fasL: 3,56). Os níveis de RNAm de bid (0,10; p=0,001) e bok (0,72; p=0,006) estavam elevados no pré-mob em relação ao grupo controle (bid: 0,004; bok: 0,31). As moléculas bcl-2, bcl-w, bcl-xL, mcl-1, bad, bax, bok, fasL e cIAP-1 atingiram níveis de RNAm similares aos controles após o TACTH. Foi verificado que a expressão de bcl-w, cIAP-1 e noxa estava maior nos pacientes com DM-1 em remissão quando comparados àqueles em recaída. A diminuição da expressão de a1, bcl-2 e bcl-w e o aumento de fas e noxa correlacionaram-se às porcentagens de hemoglobina glicosilada, concentração de auto-anticorpos GAD65, e aos níveis séricos de peptídeo-C após o transplante. Os pacientes com EM mostraram uma expressão reduzida dos genes anti-apoptóticos bcl-w (0,11; p=0,02) e cIAP-1 (1,87; p=0,04) no pré-mob comparada aos valores dos controles (bcl-w: 0,27; cIAP-1: 7,75) e maior expressão dos genes a1 (90,8; p=0,001) e cIAP-2 (58,8; p=0,009) em relação aos controles (a1: 12,7; cIAP-2: 22,3). As moléculas pró-apoptóticas bad (0,007; p=0,01) e bax (0,0007; p=0,004) mostraram menor expressão nas CMN no período pré-mob do que nos controles (bad: 0,27; bax: 1,24). Os genes bid (20,7; p=0,004), bik (0,84; p=0,02) e bok (1,77; p=0,0001) possuíam maior expressão no período pré-mob em relação aos indivíduos sadios (bid: 2,64; bik: 0,33; bok: 0,26). Não foram observadas diferenças significativas na expressão das moléculas da via extrínseca da apoptose nos pacientes com EM (p>0,05) nos períodos avaliados. Os valores de expressão de bcl-w, bak, bax, bik, bok e cIAP-1 atingiram níveis semelhantes aos controles após o transplante. A expressão dos genes bcl-2, cIAP-1, bad e bax estava maior nos pacientes em remissão da EM quando comparados àqueles em progressão neurológica. O aumento da expressão dos genes pró-apoptóticos bax, bak e bimEL correlacionou-se inversamente aos valores de EDSS dos pacientes com EM após o TACTH. Os resultados de expressão protéica foram equivalentes aos de expressão gênica nas duas doenças, com exceção dos dados das proteínas Bcl-2 e Bim. Em conjunto, os resultados demonstraram a desregulação da expressão de várias moléculas anti- e pró-apoptóticas nas CMN dos pacientes com DM-1 e EM. Esses achados sugerem a associação de alterações nos processos de apoptose celular com o surgimento e persistência de células auto-reativas no DM-1 e EM. Os dados indicam que essas alterações, principalmente a diminuição da expressão de moléculas pró-apoptóticas, como bak e bax, possam contribuir para a patogênese do DM-1 e EM. Além disso, a terapia de IAD/TACTH foi capaz de modular a expressão da maioria dos genes anormalmente expressos nas CMN dos pacientes com DM-1 e EM, já que esses atingiram níveis de expressão similares ao grupo controle após o transplante. Esta normalização da expressão de vários genes analisados correlacionou-se com a remissão clínica da doença na maioria dos pacientes
Type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) are inflammatory, organ-specific autoimmune diseases characterized by selective destruction of insulin-producing pancreatic -cells and central nervous system, respectively, by autoreactive B and T cells. Deregulation of apoptotic machinery is supposed to contribute to self-tolerance breakdown and autoimmune diseases pathogenesis, since apoptotic molecules have an important role in B and T lymphocytes central and peripheral tolerance mechanisms. The aim of this study was to evaluate the expression of pro and anti-apoptotic molecules from intrinsic and extrinsic apoptotic pathways and IAP Family members in 33 healthy individuals, 15 T1DM and 18 MS patients submitted to high-dose immunossupression therapy followed by autologous hematopoietic stem cell transplantation (HDI/AHSCT). Peripheral blood mononuclear cells (PBMC) were isolated from controls and patients at pre-mobilization (pre-mob), pre-conditioning (pre-cond), D+180, D+360, D+540 and D+720 post-transplantation. PBMC were used for RNA extraction, cDNA synthesis, gene quantification of a1, bcl-2, bcl-w, bcl-xL, bad, bak, bax, bid, bik, bimEL, bok, noxa, fas, fasL, c-FLIPL, cIAP-1 and cIAP-2 by Real Time PCR and Bcl-2, Bcl-xL, Bak, BimEL and c-FLIPL proteins detection by western-blotting. Results are expressed as median of relative expression units. Results from T1DM patients indicated that antiapoptotic molecules bcl-2 (median: 0,98; p=0,04), bcl-w (0,08; p=0,04), mcl-1 (1254; p=0,03) and cIAP-1 (1,24; p=0,003) were downregulated at pre-mob compared with healthy controls (medians bcl-2: 7,58; bcl-w: 0,52; mcl-1: 1659; cIAP-1: 14,5), while cIAP-2 (60,8; p=0,0005) gene expression was upregulated compared to healthy controls (23,3). We observed a significant decrease in proapoptotic bad (0,002; p<0,0001), bax (0,01; p=0,002) and fasL (1,66; p=0,001) genes expression in patients PBMC at pre-mob period compared to healthy subjects (bad: 0,23; bax: 2,79; fasL: 3,56). mRNA levels of bid (0.10; p=0.001) and bok (0.72; p=0.006) were elevated at pre-mob period when compared to control group (bid: 0.004; bok: 0.31). The bcl-2, bcl-w, bcl-xL, mcl-1, bad, bak, bax, bok, fasL and cIAP-1 mRNA levels reached controls levels after HDI/AHSCT. We observed that bcl-w, cIAP-1 and noxa gene expression were increased in T1DM patients in remission when compared to relapsed patients. The decreased antiapoptotic gene expression and increased in proapoptotic molecules correlated with decreased glicosilated hemoglobin percentages (Hb A1C) and anti-GAD65 antibodies and increased peptide-C levels. Results from MS patients showed decreased bcl-w (0,11; p=0,02) and cIAP-1 gene expression (1,87; p=0,04) in patients PBMC at pre-mob period compared to healthy controls (bcl-w: 0,27; cIAP-1: 7,75) and increased expression of a1 (90,8; p=0,001) and cIAP-2 (58,8; p=0,009) compared to controls (a1: 12,7; cIAP-2: 22,3). Proapoptotic molecules bad (0.007; p=0.01) and bax (0.0007; p=0.004) showed decreased gene expression at pre-mob compared to control group (bad: 0.27; bax: 1.24). bid (20.7; p=0.004), bik (0.84; p=0.01) and bok genes (1.77; p=0.0001) showed increased expression at pre-mob compared to healthy controls (bid: 2.64; bik: 0.33; bok: 0.26). Significant differences were not observed in the expression of the extrinsic pathway genes in pre-mob and healthy controls samples (p>0.05). bcl-w, bak, bax, bik, bok and cIAP-1 expression values reached healthy control values after transplantation. We observed that bcl-2, cIAP-1, bad and bax gene expression was increased in MS patients in disease remission when compared to patients with neurologic progression. Significant correlation of increased proapoptotic genes expression with decreased EDSS values in MS patients after HDI/AHSCT was observed. Results of protein quantification of apoptotic molecules in PBMC of T1DM and MS patients were similar to the gene expression results of these molecules, except for Bcl-2 and Bim proteins. Taken together, these data indicate a deregulated expression of anti- and proapoptotic genes in T1DM and MS patients PBMC. These data suggest an association of deregulated apoptosis with emergence and maintenance of autoreactive lymphocytes in analyzed patients. Based on these results, we suggest that this altered gene expression profile, mainly the decreased proapoptotic genes expression, as bak and bax, may contribute to T1DM and MS pathogenesis. Furthermore, we showed that the HDI/AHSCT therapy was able to modulate and normalize the expression of most genes abnormally expressed in T1DM and MS patients at pre-transplant period. Many analyzed genes achieved expression levels similar to healthy controls. The normalization of the expression of many evaluated genes correlated to disease remission in the majority of the patients.

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Wärnberg, Fredrik. „Prognosis in carcinoma in situ of the breast“. Doctoral thesis, Uppsala University, Department of Surgical Sciences, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-484.

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The incidence of breast cancer is rising steadily in Sweden and the proportion of carcinoma in situ (CIS) has increased appreciably, most likely due to mammography screening. The aim of this study was twofold: (1) to examine risk factors for subsequent invasive breast carcinoma and breast cancer death after primary ductal carcinoma in situ (DCIS) and (2) to study the biology in the progress between in situ and invasive carcinoma.

In a cohort-study based on 3,398 women with a primary CIS reported to the Swedish Cancer Registry (SCR) 1980-1992, women diagnosed in 1989-1992 ran a relative risk of 0.1 (CI 95%, 0.0-0.9) from dying of breast cancer as compared with women diagnosed in 1980-1982. Women in counties with mammography screening ran a relative risk of 0.2 (CI 95%, 0.0-2.1) for breast cancer death in comparison with women in non-screening counties.

In a case-control study derived from all 4,661 women with primary CIS reported to the SCR 1960-1992, we investigated risk factors for subsequent invasive breast carcinoma (n=118) and breast cancer death (n=39). Large size and multifocality were found to increase the risk for breast cancer death. Postoperative radiotherapy and mastectomy lowered the risk for ipsilateral invasive cancer.

The standardised incidence rates (SIR) for invasive breast cancer were estimated in the cohort from 1980-1992. The SIR after primary DCIS and primary lobular carcinoma in situ (LCIS) was 4.5 (CI 95%, 3.7-5.5) and 4.0 (CI 95%, 2.1-7.5), respectively.

New histopathological classification systems for DCIS were evaluated in 195 women consecutively diagnosed with primary DCIS between 1986-1994. One group with highly differentiated lesions was defined with the EORTC classification system and had an excellent prognosis.

Histopathological grade and expression of p53, c-erbB-2, Ki 67, hormone receptors, Bcl-2 and angiogenesis were compared in 626 women with either a pure DCIS, a small invasive carcinoma or a lesion with both an invasive and in situ component. When grade was taken into account, no change in tumour markers could be detected that signalled the progression from an in situ stage to invasiveness. All tumour markers correlated to grade and their distribution was very similar in the two components of mixed lesions.

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Shiau, Chung-Wai. „Thiazolidinediones: from peroxisome-proliferator-activated receptor γ(PPARγ) to anticancer agents“. The Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1128111032.

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Skírnisdóttir, Ingirídur. „Prognostic Factors in Early Stages (FIGO I-II) of Epithelial Ovarian Carcinoma“. Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1729.

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From January, 1988, to December, 1993, 113 patients with FIGO stage IA-IIC epithelial ovarian carcinoma were treated with postoperative radiotherapy. The median follow-up period was 74 months. Tumor recurrences were recorded in 33 cases (30%). The cancer-specific survival rate was 72%. Tumor grade was a significant (P = 0.007) and independent prognostic factor in the multivariate analysis. In a smaller series of 106 patients, a number of prognostic factors (age, FIGO stage, histopathological type, and tumor grade) were studied in relation to regulators of apoptosis (p53, bcl-2, and bax) and growth factor receptors (HER-2/neu and EGFR). Immunohistochemical techniques were used. In a separate series of 103 patients, the DNA content (flow cytometry) and p53 status of the tumors were also studied and related to the same clinicopathological factors. P53 was associated with tumor grade (P = 0.007) and survival status (P = 0.046). In a Cox multivariate analysis, tumor grade (P = 0.0006), bax status (P = 0.020), and EGFR status (P = 0.018) were significant and independent prognostic factors. DNA ploidy of the tumors was strongly associated with tumor grade.

From January, 1994, to December, 1998, a series of 109 patients with ovarian carcinomas (FIGO IA-IIC) were treated with postoperative adjuvant chemotherapy. The same prognostic factors were studied in this series. The median follow-up was 48 months and the cancer-specific survival rate was 75%. Twenty-five (25%) tumor recurrences were recorded. The most favorable survival rate was seen in patients with tumors negative for p53 and positive for bcl-2 or bax. In a multivariate analysis, tumor grade (P = 0.014) and p53 status (P = 0.020) were independent prognostic factors.

Clinical, histopathological and biological prognostic factors should be combined in prognostic models to render patient-tailored therapy possible and to define different prognostic groups for future clinical studies of adjuvant therapy in early stage ovarian carcinomas.

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Elledge, C. D. Resurrection of the Dead in Early Judaism, 200 BCE-CE 200. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780199640416.001.0001.

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Belief in resurrection of the dead became one of the most adamant conceptual claims of Christianity and rabbinic Judaism. This book provides a focused analysis of the gradual emergence and diverse receptions of the discourse of resurrection within early Jewish literature, from its early emergence within portions of 1 Enoch (c.200 BCE), until its standardization as a non-negotiable eschatological belief in the Mishnah (c.CE 200). Within this historical environment, resurrection emerged as an insurgent and controversial theodicy that challenged more traditional interpretations of death. The study further demonstrates how scribal circles legitimated the controversial eschatological claim by clothing it in the raiment of earlier scriptural language, grounding it in the theology of creation, and insisting that it was essential to the affirmation of divine justice. As resurrection gained a reception in multiple movements within early Judaism, a diverse range of conceptions flourished, including a fascinating variety of assumptions about the embodied character of eschatological life, as well as how resurrection would transpire within larger cosmic-spatial parameters of the world. The hope also maintained a somewhat tensive relationship with belief in the immortality of the soul, another popular approach to the afterlife within early Judaism. Supportive chapters explore the emergence of resurrection within specific literary texts and collections, including 1 Enoch, the Dead Sea Scrolls, Josephus, 4 Ezra, 2 Baruch, and select inscriptions. As the nascent church and early rabbinic Judaism developed their own approaches to resurrection, they remained both the heirs and creative reinterpreters of earlier Jewish theologies of resurrection.

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Buchteile zum Thema "Bcl-2 Receptors"

Blom, B., H. Spits und P. Krimpenfort. „The Role of the Common Gamma Chain of the IL-2, IL-4, IL-7 and IL-15 Receptors in Development of Lymphocytes. Constitutive Expression of Bcl-2 does not Rescue the Developmental Defects in Gamma Common-Deficient Mice“. In Cytokines and Growth Factors in Blood Transfusion, 3–11. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4613-1137-9_1.

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Sheikh, M. Saeed, und Ying Huang. „TRAIL Death Receptors, Bcl-2 Protein Family, and Endoplasmic Reticulum Calcium Pool“. In TRAIL (TNF-Related Apoptosis-Inducing Ligand), 169–88. Elsevier, 2004. http://dx.doi.org/10.1016/s0083-6729(04)67010-5.

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Konferenzberichte zum Thema "Bcl-2 Receptors"

Mayeenuddin, Linnia H., Yunkai Yu, Zhigang Kang, Lee J. Helman und Liang Cao. „Abstract 701: Elevated insulin-like growth factor 1 receptor provides an essential survival signal via Bcl-xLin rhabdomyosarcoma cells as an alternative to Bcl-2 overexpression“. In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-701.

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Whittle, JR, F. Vaillant, AN Policheni, K. Liu, B. Pal, G. Giner, K. Fernandez et al. „Abstract PD7-07: Synergistic targeting of CDK4/6 and BCL-2 pathways in estrogen receptor positive breast cancer“. In Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-pd7-07.

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Wang, Ziqian, Zhichao Zhang, Ting Song und Zongwei Guo. „Abstract 2754: Affinity-based probe reveal Bim negatively regulates the chaperone functions of Hsp70, a non-Bcl-2 BH3 receptor“. In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2754.

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Nii, Takenobu, Jo Ishizawa, Varun V. Prabhu, Vivian Ruvolo, Neel Madhukar, Ran Zhao, Hong Mu et al. „Abstract 4957: The novel imipridone ONC212 highly synergizes with the BCL-2 inhibitor ABT-199 in AML and activates orphan receptor GPR132“. In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-4957.

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Fang, Douglas D., Qiuqiong Tang, Ran Tao, Guoqin Zhai, Qixin Wang, Dajun Yang und Yifan Zhai. „Abstract 6233: APG-2575, a clinical stage BCL-2 selective inhibitor, sensitizes estrogen receptor-positive breast cancers to standard therapies in the preclinical models“. In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-6233.

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Sudrajat, Ahmad, und Maisuna Kundariati. „Study in Silico Alkaloid Compounds Tapak Dara Plant (Catharanthus roseus (L) G. Don) on Antiapoptosis Receptor B-Cell Lymphoma-2 Regulator (Bcl-2) as Anti-Cancer Chronic Lymphocytic Leukemia (CLL)“. In Proceedings of the 2nd International Conference on Quran and Hadith Studies Information Technology and Media in Conjunction with the 1st International Conference on Islam, Science and Technology, ICONQUHAS & ICONIST, Bandung, October 2-4, 2018, Indonesia. EAI, 2020. http://dx.doi.org/10.4108/eai.2-10-2018.2295578.

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Gee, JM, MA Aleskandarany, P. Finlay, L. Farrow, RI Nicholson, HO Habashy, AR Green et al. „Abstract P2-09-37: Immunohistochemical Markers Progesterone Receptor, HER2, Ki67 and bcl-2-Associated Athanogene 1 and Prediction of Adjuvant Tamoxifen Treatment Outcome in ER+ Early Breast Cancer“. In Abstracts: Thirty-Third Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 8‐12, 2010; San Antonio, TX. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/0008-5472.sabcs10-p2-09-37.

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Shouse, Geoffrey P., Rosalia de Necochea-Campion, Saied Mirshahidi, Chien-Shing Chen und Kimberly J. Payne. „Abstract 5442: Dose-dependent toxicity of FTY720, a sphingosine-1-phosphate receptor agonist, on double hit lymphoma cells via PP2A-mediated dephosphorylation of c-myc and bcl-2“. In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5442.

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Henson, Elizabeth S., Teralee R. Burton, Meghan B. Azad, David D. Eisenstat und Spencer B. Gibson. „Abstract 4108: BH3 only Bcl-2 family member BNIP3 repressed expression of death receptor 5 (DR5) in glioblastoma cells: Implications for regulation of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) cell death pathway“. In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-4108.

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