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STELLA, MARTINA. « Identification of molecular alterations associated with the progression of clear cell Renal Cell Carcinoma by mass spectrometric approaches ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241159.
Texte intégralRésumé :
Il carcinoma a cellule renali rappresenta la più frequente forma di tumore al rene, e il carcinoma a cellule chiare ne è il morfotipo più ricorrente (80% dei casi). Ad oggi la nefrectomia, totale o parziale, rimane il trattamento di elezione. E’ evidente, quindi, la necessità di indagare a fondo gli aspetti molecolari associati alla progressione del tumore, con il fine ultimo di produrre conoscenze utili alla diagnosi o trattamento delle lesioni stesse. In questo lavoro abbiamo utilizzato approcci proteomici complementari per lo studio dei processi associati all’insorgenza e alla progressione (stadio e grado) dei tumori: Matrix-Assisted Laser Desorption/Ionisation – Mass Spectrometry Imaging (MALDI-MSI) e nLC-ESI MS/MS. Combinando l’utilizzo di fluidi biologici, che non richiedono tecniche invasive, e l’analisi diretta del tessuto tumorale, abbiamo approfondito lo studio delle modifiche proteomiche associate alla progressione del carcinoma renale a cellule chiare. Inizialmente abbiamo considerato le informazioni ottenibili da diversi fluidi biologici: urine e plasma. Abbiamo quindi valutato la distribuzione spaziale di peptidi triptici in aree del tumore a diversi gradi (MALDI-MSI), associandovi l’analisi di omogenati di tessuto per aumentare le informazioni quali-quantitative ottenibili (nLC-ESI MS/MS). Infine, abbiamo mostrato come informazioni relative alla dimensione e allo stadio della lesione siano rilevabili anche dalle urine del paziente. Attualmente sono in corso studi più approfonditi sui processi biologici coinvolti e dati preliminari suggeriscono un ruolo fondamentale dei processi metabolici nella progressione del tumore. Inoltre, è stato messo a punto un protocollo per l’analisi di N-glicani direttamente da tessuto, che sarà utilizzato per valutare la loro espressione in diverse aree del tumore. In conclusione, siamo fiduciosi che tutti i dati raccolti possano portare a una miglior comprensione dei processi coinvolti nella progressione del tumore renale a cellule chiare.Renal Cell Carcinoma (RCC) is the most frequent form of kidney cancer and approximately 80% of cases are defined as clear cell RCC (ccRCC). Partial or total nephrectomy remain the gold standard for the routine treatment of ccRCC, therefore a better understanding of molecular aspects associated to tumour progression could be useful for its diagnosis, prognosis and treatment. Nowadays proteomic approaches are more readily used to investigate the processes that drive disease onset and progression. In this work, two complementary technologies, Matrix-Assisted Laser Desorption/Ionisation – Mass Spectrometry Imaging (MALDI-MSI) and nLC-ESI MS/MS, were used to detect alterations within tumour lesions and to perform protein identification and quantification. Likewise, employing both tissue and body fluids (urine-plasma) ensures a strong correlation with the disease, a high degree of lesion specificity whilst at the same time enables the use of more readily accessible samples. Therefore, the aim of this study was to investigate proteomic changes in different human specimens related to early pathological modifications and ccRCC progression. Our study on ccRCC started with the evaluation of the information that can be obtained from urine and plasma from patients with ccRCC. Then, MALDI-MSI was used to evaluate the spatial distribution of tryptic peptides directly on tissue, and the molecular data has been correlated to morphological annotation (grade). Moreover, in situ findings has been combined with those obtained from tissue homogenates and better understanding of molecular changes among the four grades has been provided. Finally, we demonstrate the possibility to detect in urine alterations determined by the stage of the lesion. Further work related to the study of ccRCC tissue is currently ongoing. At first, the biological role of the proteins resulted to be altered and the pathways involved in grade progression are under investigation. Preliminary data suggest the essential role of metabolic alterations in ccRCC progression. Moreover, a protocol for realised N-glycans analysis directly on tissue has been optimised and this protocol will be used to evaluate N-glycans trait on different ccRCC grade areas. In conclusion, it is hoped that the data obtained along with the additional work planned, could better clarify the biological processes involved in ccRCC progression.
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SQUEO, VALERIA. « Alterazioni del peptidoma serico di pazienti con tumore renale valutate tramite "label-free" (nLC-ESI-MS/MS) e "peptide profiling" (MALDI-MS/MS) ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/43783.
Texte intégralRésumé :
Il progetto di questa ricerca è stato rivolto allo studio e alla caratterizzazione del peptidoma serico di soggetti sani e pazienti con carcinoma renale, così come alla diagnosi differenziale delle forme di tumore renale maligno da lesioni benigne. A questo proposito sono stati purificati, mediante tecnica ClinProt che utilizza microparticelle
magnetiche funzionalizzate, il siero di un ampio numero di pazienti affetti da ccRCC e soggetti controllo, estendendo lo studio anche a pazienti affetti da non-ccRCC. Le analisi di profiling peptidico sono state condotte mediante SM MALDI-TOF seguita da elaborazione dei profili spettrali per all’individuazione di clusters con potenziale diagnostico. Inoltre si è cercato di identificare proteine/peptidi con alterata espressione serica. A questo scopo sono state effettuate analisi mediante tecnologia nLC-ESI MS/MS e MALDI-TOF MS/MS. I risultati del "profiling" tramite MALDI-TOF sono stati verificati utilizzando un approccio proteomico diverso basato su una quantificazione relativa label-free in nLC-ESI MS/MS.
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Pedro, Renato Nardi. « Uso da nanopartícula de ouro ligada a moléculas de fator alfa de necrose tumoral como adjuvante da termoablação por radiofrequência de tumores renais = modelo animal experimental ». [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310676.
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Orientadores: Marcelo Lopes de Lima, Nelson Rodrigues Netto JuniorTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-17T00:02:35Z (GMT). No. of bitstreams: 1 Pedro_RenatoNardi_D.pdf: 3805668 bytes, checksum: 8b1ea901163cf75ede5f727e7f455e0c (MD5) Previous issue date: 2010
Resumo: O tratamento definitivo das massas renais malignas é primordialmente cirúrgico, sendo a nefrectomia radical eleita por muitos anos a cirurgia padrão para o tratamento do câncer renal localizado. Entretanto, com o envelhecimento populacional, maiores são as preocupações em se manter a capacidade funcional dos órgãos e sistemas do corpo humano. Portanto, a necessidade de se preservar tecido renal sadio durante o tratamento do câncer renal localizado, com auxílio de cirurgias parciais poupadoras de néfrons, se tornou imperativa. O tratamento de lesões renais sólidas pequenas passou a ter diferentes formas de abordagem, que variam desde técnicas de termoablação percutânea ou laparoscópica, nefrectomia parcial laparoscópica e aberta à até tradicional nefrectomia radical aberta. O uso de modalidades de tratamento cirúrgico com mínimo grau de agressão passou a ganhar atenção, devido à rápida recuperação do paciente, ao menor risco de complicações cirúrgicas e aos bons resultados oncológicos. Ablação por radiofreqüência (ARF) tem se mostrado um meio eficiente no tratamento de tumores renais pequenos e exofiticos. Atualmente, sua indicação é restrita a lesões de até 4 cm. O presente estudo foi montado para avaliar o uso conjunto da nanopartícula de ouro e fator alfa de necrose tumoral (TNF alfa) à ARF no tratamento de um modelo experimental de tumor renal. Materiais e Métodos: Trinta e sete coelhos brancos da raça New Zealand tiveram implantados em seus rins, através de uma laparotomia, um fragmento de 1 mm3 de tumor VX-2. Após 14 dias do implante, quando seus rins haviam desenvolvido uma lesão tumoral sólida menor que 1 cm, os animais foram divididos em 3 grupos de 10 e 1 grupo de 7 integrantes (sham) de acordo com o tratamento selecionado para o tumor renal focal: 1) Nanopartícula com TNF alfa; 2) Ablação por radiofreqüência; 3) Nanopartícula com TNF alfa seguido de Ablação por radiofreqüência; 4) Grupo sham. Todos os animais foram submetidos a mesma cronologia de tratamento, composta por 2 laparotomias e eutanásia. Os grupos tratados com as nanopartículas de ouro com fator alfa de necrose tumoral isolada ou complementarmente, as receberam 4 horas antes do procedimento cirúrgico na dose de 200 µm/Kg. A análise de resultados foi realizada com medidas macroscópicas e microscópicas do volume da área de ablação ou tumoral, segundo a fórmula do volume de uma elipsóide. Avaliação estatística foi realizada com Teste T Student, sendo considerado significante p<0.05. Resultados: O grupo que recebeu a nanopartícula com fator alfa de necrose tumoral e depois foi submetido à ARF apresentou maior zona de morte celular completa quando comparado ao grupo tratado somente com ablação por radiofreqüência (0.30 ± 0.07 vs 0.23 ± 0.03 mL, P=.03). A zona de transição foi menor no grupo que recebeu a nanopartícula com fator alfa de necrose tumoral e ablação por radiofreqüência quando comparada ao grupo tratado somente com ablação por radiofreqüência (0.08 ± 0.02 vs 0.13 ± 0.05 mL, P =.01). Conclusão: O presente estudo demonstrou que o uso da nanopartícula de ouro com TNF alfa sensibiliza o insulto térmico sofrido por tumores sólidos decorrentes da ablação por radiofreqüência
Abstract: Radical nephrectomy has long been considered as gold standard treatment for localized renal tumors. However due to an increase in life expectation, organ sparing surgeries have emerged with the purpose of preserving as much healthy tissue as possible. Therefore, nephron sparing surgeries have become another valid option for localized renal tumors. There are different modalities of nephron sparing procedures, including open partial nephrectomy, laparoscopic nephrectomy and termoablative procedures. The later is associated with less morbidity and fast patient recovery. Radiofrequency ablation (RFA) is a well-known termoablative procedure and it has been most effective when the tumors are small, exophytic, and away from vital structures. The present study was designed to analyze the adjuvant use of gold nanoparticle with tumor necrosis factor alpha prior to radiofrequency ablation in a translational model of localized renal tumor. Material and Methods: A total of 37 New Zealand White rabbits had VX-2 tumors implanted into their kidneys; they were allowed to grow for 14 days, when a tumor mass of less than 1 cm could be detected. The animals were then split into 3 treatment groups of 10 rabbits each and a sham group of 7 rabbits as follows: (1) Tumor necrosis factor alpha plus nanoparticle, (2) Radiofrequency ablation, (3) Tumor necrosis factor alpha nanoparticle (200 µm/Kg) followed 4 hours later by radiofrequency ablation. All groups were subjected to the same milestones of the experiment which was comprised of 2 laparotomies and sacrification. Gross and microscopic measurements of the ablation size as well as histological analysis using hematoxylin and eosin staining were performed to determine the effect of TNF alpha nanoparticle on the ablation. Statistical analysis was performed with Student's T test, considering p < 0.05 as significant. Results: The RFA plus TNF alpha nanoparticle group had a larger zone of complete cell death than the RFA-only group (0.30 ± 0.07 vs 0.23 ± 0.03 mL, P=.03). The zone of partially ablated tissue was smaller in the RFA plus TNF alpha nanoparticle group than in the RFA-only group (0.08 ± 0.02 vs 0.13 ± 0.05 mL, P =.01). Conclusions: We have demonstrated the efficacy of TNF alpha nanoparticle in enhancing RFA in a translational kidney tumor model. The potential usage of TNF alpha nanoparticle to improve RFA of renal cell carcinoma merits further study
Doutorado
Fisiopatologia Cirúrgica
Doutor em Ciências
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Andersson, Charlotta. « Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors ». Doctoral thesis, Umeå universitet, Institutionen för medicinsk biovetenskap, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-120912.
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Wilms’ tumor gene 1 (WT1) is a zinc finger transcriptional regulator with crucial functions in embryonic development. Originally WT1 was described as a tumor suppressor gene, but later studies have shown oncogenic properties of WT1 in a variety of tumors. Because of its dual functions in tumorigenesis, WT1 has been described as a chameleon gene. In this thesis, the significance of WT1 as a biomarker was investigated in acute myeloid leukemia (AML), clear cell renal cell carcinoma (ccRCC), ovarian carcinoma (OC) and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Previous studies have suggested that expression of WT1 is a potential marker for detection of minimal residual disease (MRD) in AML. We aimed to define expression of WT1 as an MRD marker in AML. In adult AML patients, we found that a reduction of WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis was associated with an improved overall survival (OS) and freedom from relapse (FFR). In peripheral blood, a reduction of WT1 expression (≥ 2-log) detected between 1 and 6 months after treatment initiation was associated with an improved OS and FFR. WT1 harbor pathogenic genetic variants in a considerable proportion of AML and T-lymphoblastic leukemia (T-ALL), but mutations have not been reported in BCP-ALL. We aimed to evaluate the clinical impact of WT1 mutations and single nucleotide polymorphisms (SNPs) in BCP-ALL. Pathogenic mutations in the WT1 gene were rarely seen in childhood BCP-ALL. However, five WT1 SNPs were identified. In survival analyses, WT1 SNP rs1799925 was found to be associated with worse OS, indicating that WT1 SNP rs1799925 may be a useful marker for clinical outcome in childhood BCP-ALL. We also explored whether WT1 mutations and SNPs in ccRCC could be used as biomarkers for risk and treatment stratification. We therefore examined whether SNPs or mutations in WT1 were associated with WT1 expression and clinical outcome. Sequencing analysis revealed that none of the previously reported WT1 mutations were found in ccRCC; however, we identified six different WT1 SNPs. Our data suggest that pathogenic WT1 mutations are not involved in ccRCC, and the prognostic significance of WT1 SNPs in ccRCC is considerably weak. However, a favorable OS and disease-specific survival were found in the few cases harboring the homozygous minor allele. OC has a poor prognosis, and early effective screening markers are lacking. Serous OCs are known to express the WT1 protein. Overexpressed oncogenic proteins can be considered potential candidate antigens for cancer vaccines and T-cell therapy. It was therefore of great interest to investigate whether anti-WT1 IgG antibody (Ab) measurements in plasma could serve as biomarkers of anti-OC response. We found limited prognostic impact, but the results indicated that anti-WT1 IgG Ab measurements in plasma and WT1 staining in tissue specimens could be potential biomarkers for patient outcome in the high-risk subtypes of OCs. In conclusion, the results of this thesis indicate that WT1 gene expression can provide information about MRD of patients with AML, and WT1 SNP rs1799925 may be used as a biomarker for predicting clinical outcome in childhood BCP-ALL. In ccRCC, the prognostic significance of WT1 SNPs is weak and limited to the subgroup of patients that are homozygous for the minor allele. In OCs anti-WT1 IgG Ab measurement in plasma and WT1 staining in tissue specimens could possibly be used as biomarkers for predicting patient outcome in the high-risk subtypes of OCs.
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Patrício, Patrícia Carvalho. « Analysis of PAX2 gene alterations in renal cell tumors ». Master's thesis, Faculdade de Ciências e Tecnologia, 2010. http://hdl.handle.net/10362/10574.
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Dissertation for applying to a Master’s Degree in Molecular Genetics and Biomedicine submitted to the Sciences and Technology Faculty of New University of LisbonBackground: Renal cell tumors (RCT) represent a heterogeneous group of malignancies arising from the epithelium of the renal tubules. PAX2 (Paired-box 2) is a transcription factor belonging to the evolutionarily conserved paired-box family that is required during development of the central nervous system and genitourinary tract. PAX2, which is considered a proto-oncogene, is normally suppressed at the later stages of embryonic development and reactivated during the carcinogenic process in some cancer models. Previously published data indicate that significant expression of PAX2 protein occurs in three of the most prevalent renal cell tumor subtypes - clear cell RCC (ccRCC), papillary RCC (pRCC) and oncocytoma - but not in chromophobe RCC (chrRCC). Moreover, it has been reported that PAX2 expression could be repressed by aberrant methylation at the end of nephrogenesis. Finally, FISH and cytogenetic analysis, demonstrated loss of chromosome 10 (to which PAX2 is mapped) in 40 to 60% of chrRCC cases. Aims: The main goal of this study was to identify epigenetic and/or genetic alterations affecting the PAX2 gene in a series of renal cell tumors, representing the four major subtypes. Specifically, our aims were to: (1) analyze the expression of PAX2 in different renal cell tumor subtypes, both at mRNA and at protein level; (2) determine whether the regulation of PAX2 expression occurs by epigenetic mechanisms, by assessing its promoter methylation status; (3) analyze the association between PAX2 copy number and gene expression; (4) evaluate the potential use of PAX2 epigenetic/genetic alterations as a biomarker for discrimination between chrRCC and oncocytoma. Methodology: In this study, 120 samples of renal cell tumors (30 of each subtype: ccRCC, pRCC, chrRCC, and oncocytoma) and 4 normal kidney tissues were tested. First, PAX2 protein expression was assessed by immunohistochemistry and the PAX2 mRNA expression levels were determined by quantitative reverse transcription PCR (qRT-PCR), using HPRT1 as an endogenous control. The methylation status of PAX2 promoter was assessed by methylation-specific PCR using two different sets of primers that annealed to adjacent regions in the promoter. The relationship between the number of PAX2 copies and its expression in chrRCC was analyzed by FISH. The chi-square test or Fisher’s exact test were used to seek for differences in the frequency of immunoreactivity for PAX2 protein among the four RCT subtypes....
CI-IPOP-4 and the Calouste Gulbenkian Foundation (Project # 96474)
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Dijkhuizen, Trijntje. « Genetic contributions to the classification of renal cell cancer ». [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1997. http://irs.ub.rug.nl/ppn/159282535.
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Hudon, Valerie. « Investigating tumor suppressor genes involved in renal cell carcinomas ». Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86607.
Texte intégralRésumé :
Kidney cancer is a complex disease comprising several types of renal carcinomas, which are classified in different subtypes based on their histological characteristics. A small number of cases of renal cancers are due to hereditary predispositions and nearly all the knowledge on the molecular pathogenesis of kidney cancers was learned by the investigation of these hereditary forms of renal carcinomas. In this thesis, we studied two hereditary diseases predisposing to the development of kidney cancer, von Hippel Lindau (VHL) and Birt-Hogg-Dubé (BHD) syndromes, and their causative genes, VHL and FLCN respectively. First, we investigated the role of the extracellular matrix (ECM) regulation by VHL during tumorigenesis and angiogenesis, and we demonstrated that inactivation of the VHL-ECM assembly pathway results in highly vascularized tumors with a disrupted ECM. We concluded that loss of the ECM assembly promotes and maintains tumor angiogenesis by providing a way for new blood vessels to invade the tumor tissue. In the second part of this thesis, we developed a novel VHL mouse model to investigate the possible cooperation between VHL and p53 during tumorigenesis. We observed that inactivation of both tumor suppressor genes accelerate the formation of liver hemangiomas and splenic hemangiosarcomas. Furthermore, concomitant deletion of VHL and p53 abolished the development of lymphoma usually associated with loss of p53. Our results indicate that the phenotypes arising following the inactivation of VHL and p53 is organ-dependent. Finally, to study the pathogenesis of the BHD syndrome, we developed a new mouse model using an established embryonic stem cell line. We described the murine Flcn expression pattern and noticed that homozygous disruption of Flcn was embryonically lethal early during development. Furthermore, we observed a continuum of kidney lesions from renal tubules hyperproliferation to rare adenoma. FLCN tumor suppressor role was also substantiated usiLe cancer du rein est une maladie complexe qui comprend différents types de cancers classifiés selon leurs caractéristiques histologiques. Certains cas de cancers rénaux sont attribuables à une prédisposition héréditaire et l'étude de ces formes héréditaires de cancer a largement contribué au développement des connaissances concernant la pathogenèse des cancers rénaux. Le travail décrit dans cette thèse porte sur deux maladies héréditaires prédisposant au développement de tumeurs rénales soit la maladie de Von Hippel-Lindau (VHL) et le syndrome de Birt-Hogg-Dubé (BHD) ainsi que les gènes associés à ces dernières, VHL et FLCN respectivement. Premièrement, nous avons étudié le rôle de la régulation de l'assemblage de la matrice extracellulaire (MEC) par VHL durant la tumorigénèse et nous avons démontré que l'assemblage inadéquat de la MEC corrèle avec une croissance tumorale accrue et induit la formation de tumeurs fort vascularisées. Nous avons conclu que la perte de l'intégrité de la MEC favorise l'angiogénèse tumorale en fournissant une voie permettant aux vaisseaux sanguins d'infiltrer la tumeur. Deuxièmement, nous avons développé un modèle murin pour étudier la coopération potentielle entre VHL et p53 durant le développement tumoral. Nous avons observé que l'inactivation simultanée de VHL et p53 accélère la progression d'hémangiomes du foie et d'hémangiosarcomes de la rate. De plus, la perte concomitante de VHL et p53 inhibe le développement de lymphomes normalement associés à l'inactivation de p53. Nos résultats indiquent que les phénotypes apparaissant suite à l'inactivation de VHL et p53 varient selon l'organe étudié. Finalement, nous avons développé un modèle murin pour étudier de la pathologie associée au syndrome BHD et à avons observé la formation d'un continuum de lésions rénales allant de l'hyperprolifération des tubules rénaux à de rares adénomes. Finalement, nous avons conf
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Anderson, Jane Ann. « Autotaxin expression in bladder and renal cancer ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6946/.
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Autotaxin is an extracellular enzyme that generates lysophosphatidic acid (LPA). LPA binds up to six different cell surface G protein-coupled receptors to initiate signaling resulting in cell survival, invasion and angiogenesis. For this reason autotaxin has emerged as a therapeutic target in several different malignancies. I have used immunohistochemistry to explore the expression of autotaxin and its correlation with clinico-pathological variables in bladder and renal cancer. I show that in bladder cancer, tumours from patients with muscle invasive disease were significantly more likely to show strong autotaxin expression than were those tumours from patients without evidence of muscle involvement (p=0.009). This observation is not only consistent with the known functions of autotaxin/LPA in promoting tumour invasion, but suggests that the potential use autotaxin inhibitors in preventing bladder cancer progression warrants further investigation. Although I failed to detect autotaxin expression in the tumour cells of patients with renal cancer, I did observe high-level expression of autotaxin on the tumour-associated vasculature, which in many cases was not apparent in blood vessels of matched normal renal tissues. This points to an important role for autotaxin in renal cancer-associated angiogenesis and suggests a potential role for autotaxin inhibition as an anti-angiogenesis therapy.
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Faust, Bethany, Candelaria MD Deimundo-Roura, Cara E. MD-PhD Marin et Marcela MD Popescu. « Cystic Nephroma in a Child with DICER1 Mutations ». Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/asrf/2021/presentations/48.
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Cystic nephromas are rare, multiloculated cysts on the kidneys that occur mostly in early childhood. They are considered to be on the same spectrum as cystic partially differentiated nephroblastomas (CPDN) and Wilm’s tumors (WT). They are mostly benign, however, when cystic nephroma is associated with DICER1 mutation, the patient is predisposed to other, more aggressive tumors. DICER1 mutations are not seen in CPDN or WT, so molecular evaluation can help differentiate between them if the histology is unclear. The DICER1 gene is on chromosome 14 and it functions to make microRNA that attaches to mRNA and represses protein synthesis. Mutations of this gene predispose patients to neoplasms on various organs such as the lung, kidneys, ovaries, and thyroid. The data in this case report was gathered via direct patient care and patient chart review. An 18-month-old previously healthy female was hospitalized for a newly diagnosed abdominal mass found on palpation during a well child evaluation. The ultrasound revealed a 9 cm cystic mass on the left kidney and the patient was subsequently sent to St. Jude Children’s Research Hospital. Further evaluation via CT scan has shown a large left renal mass that invaded the ureter and bladder, as well as enlarged lymph nodes in the left suprarenal space and a single 3mm right pulmonary nodule. At this time, cystic Wilm’s tumor was considered and the patient underwent a left radical ureteronephrectomy with lymph node sampling. Cytology report of the pelvic fluid had some inflammatory cells, but no tumor cells were seen in the sample. All of the sampled lymph nodes were also negative for tumor cells. The histological analysis of the mass revealed multiple cystic cavities separated by septa. No blastemal elements (WT1 immunostain was negative) or distinct solid areas were identified, which made the diagnosis of cystic Wilm’s tumor unlikely. The diagnosis of cystic nephroma (CN) vs cystic partially differentiated nephroblastoma (CPDN) is determined histologically by looking at the components of the septa – which, in this case, due to a marked inflammatory infiltrate expending the septa, made the morphology be more congruent with CPDN. Molecular testing of the tumoral tissue identified two DICER1 mutations (DICER1 frameshift mutation and DICER1 D1709E). Patient was subsequently diagnosed with Cystic Nephroma Stage I and further surveillance will be continued to monitor for more neoplasms associated with this mutation. This case highlights a rare disorder that predisposes patients to multiple neoplasms. Histology may not always be sufficient in determining the diagnosis, especially in differentiating CN from CPDN. Molecular evaluation may be helpful for the initial diagnosis and in order to provide adequate genetic counseling. Clinicians should be aware of DICER1 syndrome so they can adequately survey the at-risk patients for a range of benign and malignant neoplasms.
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Slater, Amy Amelia. « Epigenetic and genetic profiles of rare renal cancers ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6933/.
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The aim of this study was to characterise the genetic and epigenetic profiles of rare forms of sporadic renal cancers (RCC) and identify differential patterns of DNA methylation or somatic mutations that may permit distinction between different subtypes of RCC and could facilitate disease prognosis or identify molecular pathways that could be targeted therapeutically. Illumina Infinium HumanMethylation 450K BeadChip permitted the comparison of the epigenome of the malignant chromophobe RCC and the benign renal oncocytoma. This study identified several genes to be differentially hypermethylated in chromophobe RCC, and renal oncocytoma showing that although both visually and pathologically similar, both tumours have a distinct methylation pattern. Whole exome sequencing (WES) of renal oncocytoma samples identified somatic mutations in eighteen genes involved in a variety of cellular functions. Sanger sequencing was then used to confirm the mutations identified, followed by further screening by Sanger in a cohort of additional renal oncocytoma samples to identify if the somatic mutations are recurrent. Modern high throughput and quantitative techniques have permitted further characterisation of these rare renal cancers and have enabled unique insights into their molecular genetics, findings that may hopefully be of clinical benefit in the future.
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Jafri, Mariam. « Molecular characterisation of renal cell carcinoma and related disorders ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6996/.
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Over the last two decades genetic advances have provided novel insights into the molecular basis of familial and sporadic cancers and provided the basis for the development of novel therapeutic approaches. For example, the identification of the gene for von Hippel Lindau disease provided seminal insights into its role in most clear cell renal carcinomas (RCC) and led to new treatments for RCC. In this thesis I investigated three related genetic aspects of neoplasia. Firstly, I analyzed the results of genetic testing for inherited phaeochromocytoma and investigated how clinical features could be used to stratify patients and improve the cost effectiveness of genetic testing. Secondly, I sought to identify novel causes of inherited neoplasia. Through exome sequencing of familial RCC kindreds, \(CDKN2B\) was identified as a novel familial RCC gene. The role of \(CDKN2B\) mutations in neoplasia was evaluated in familial and sporadic RCC and phaeochromocytoma. \(In\) \(vitro\) assays confirmed that germline \(CDKN2B\) mutations associated with inherited RCC caused an abrogation of tumour suppressor function. Finally, I explored how a gene-based strategy might be used to identify novel therapeutic strategies, Thus, using a siRNA library screen, in RCC cells with inactivated \(VHL\), potential candidate targets (e.g. \({PLK1/STK}\)-\(10\)) were identified for selectively decreasing the viability of RCC cells with inactivated \(VHL\).
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Bianchi, Lorenzo <1987>. « 3D modelling per la pianificazione preoperatoria nella chirurgia conservativa dei tumori renali ». Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2022. http://amsdottorato.unibo.it/10047/1/Bianchi_Lorenzo_tesi.pdf.
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Lo scopo del progetto è quello di valutare l’impatto clinico dell’ utilizzo del 3D modeling nella pianificazione chirurgica preoperatoria della PN.
Sono stati arruolati in modo prospettico 195 pazienti con diagnosi di neoplasia renale T1 candidati a PN tra dicembre 2018 e agosto 2021. Prima dell’intervento chirurgico tutti i pazienti sono stati sottoposti a imaging 2D (TC torace-addome con mezzo di contrasto). Per valutare il ruolo e l’impatto clinico del 3D modelling sulla pianificazione chirurgica, la popolazione è stata suddivisa in due gruppi: gruppo di studio (n=100 pazienti), comprende pazienti candidati a PN dopo pianificazione chirurgica basata sia sull’imaging 2D sia sul modello virtuale 3D; gruppo di controllo (n=95) comprende pazienti candidati a PN dopo pianificazione chirurgica basata solo sull’imaging 2D. L’outcome primario dello studio è la valutazione dell’impatto della ricostruzione 3D nella pianificazione preoperatoria della PN per quanto riguarda il tasso di conversione a RN, tipo di clampaggio arterioso e la necessità di sutura del sistema caliceale.
Nei pazienti del gruppo di studio nel 77.8% dei casi la conversione a RN è stata pianificata prima della chirurgia sulla base del modello 3D, mentre nel gruppo di controllo solo nel 27.3% la conversione a RN è stata pianificata prima della chirurgia sulla base dell’imaging 2D (p=0.03). Nei pazienti sottoposti a PN, l’effettivo clampaggio arterioso eseguito durante la chirurgia è risultato significativamente differente nel gruppo di studio rispetto al gruppo di controllo con maggior tasso di clampaggi arteriosi selettivi (36.3% vs. 9.5%; p<0.001). All’analisi multivariata, solo l’utilizzo del modello 3D è risultato unico predittore indipendente di clampaggio arterioso selettivo (p≤0.001).
La revisione di modelli 3D consente una maggior tasso di conversione a RN pianificate prima della chirurgia, maggior adozione di clampaggio arterioso selettivo con maggior adesione al programma chirurgico rispetto ai pazienti sottoposti a PN con pianificazione basata su imaging 2D.The aim of the project is to evaluate the clinical impact of the use of 3D modeling in the preoperative surgical planning of PN. Overall, 195 patients diagnosed with T1 renal mass scheduled for PN between December 2018 and August 2021 were prospectively enrolled. Before surgery, all patients underwent 2D imaging (chest-abdomen CT with contrast enhancement). To evaluate the role and the clinical impact of 3D modeling on surgical planning, the population was divided into two groups: study group (n = 100 patients), includes patients who are candidates for PN after surgical planning based on both 2D imaging and on virtual 3D model; control group (n = 95) includes patients who are candidates for PN after surgical planning based only on 2D imaging. The primary outcome of the study is the evaluation of the impact of 3D reconstruction in the preoperative planning of PN with regard to the conversion rate to RN, type of arterial clamping and the need for suturing the calyceal system. In study group, 77.8% of cases the conversion to RN was planned before surgery on the basis of the 3D model, while in the control group only 27.3% of conversion to RN was planned before surgery on the basis of the 2D imaging (p = 0.03). In patients undergoing PN, the actual arterial clamping performed during surgery was significantly different in the study group compared to the control group with significantly higher rate of selective arterial clamping (36.3% vs. 9.5%; p <0.001). In multivariate analysis, only the use of the 3D model was independent predictor of selective arterial clamping (p≤0.001). Revision of 3D models allows for higher conversion rate to planned RN prior to surgery, higher adoption of selective arterial clamping with greater adherence to the surgical schedule than patients undergoing PN with 2D imaging-based planning.
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Casamayor, Barreto Albina Elena. « Evaluación tomográfica de la respuesta al tratamiento de tumores sólidos malignos pulmonares, hepáticos, colo-rectales y renales por criterios RECIST "Response Evaluation Criteria in Solid Tumor" modificado ». Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2011. https://hdl.handle.net/20.500.12672/12221.
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El documento digital no refiere asesorEvalúa objetivamente los tipos de respuesta tomográfica al tratamiento de los tumores sólidos malignos pulmonar, hepático, colo-rectal y renal con los criterios RECIST” Response Evaluation Criteria in Solid Tumor” modificado. Es un estudio retrospectivo, descriptivo y longitudinal que recopila datos tomográficos de las lesiones sólidas malignas, y datos epidemiológicos de los pacientes con diagnóstico anatomo-patológico de tumores sólidos malignos. Las respuestas finales mostraron el 60% de pacientes con progresión de la enfermedad; el 20%, con enfermedad estable; el 13%, con respuesta completa y el 7% con respuesta parcial. Conclusión: Los criterios RECIST modificado son válidos a nivel internacional y en este estudio demostraron su objetividad y utilidad en el seguimiento de las lesiones de los pacientes evaluados.
Trabajo académico
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Carretto, Elena. « Tumori rari pediatrici come spia di sindromi genetiche : un report dal progetto TREP (Tumori Rari in Età pediatrici) su carcinoma renale e feocromocitoma ». Doctoral thesis, Università degli studi di Padova, 2009. http://hdl.handle.net/11577/3426505.
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We consider rare tumors in pediatric age those tumors with an incidence less than 2 cases/1.000.000 children/year, which are not included in treatment protocols of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP). These tumors are object of a national project called TREP, aiming to register patients with rare tumors and promote studies of these cancers.
We hypothesize that infancy-onset of typically adulthood tumors, extremely rare in pediatric age, could be the expression of an underlying predisposing genetic condition. In fact, the earliest is the age of onset, the least is the exposition to environmental factors.
The renal cell carcinoma (RCC) occurs in a sporadic form or as part of genetic diseases, such as Von Hippel-Lindau disease.
Likewise, phechromocytoma and paraganglioma occur in a sporadic form or associated with hereditary disorders such as Von Hippel-Lindau disease, Hereditary Paraganglioma-Pheochromocytoma Syndrome, Multiple endocrine neoplasia type 2 (MEN2) syndrome and neurofibromatosis, type 1.
AIM
We report the preliminary results of a retrospective and prospective study of a TREP project aiming to evaluate the prevalence of main hereditary syndromes associated with renal cell carcinoma and pheochromocytoma in pediatric age.
MATERIALS AND METHODS.
Patients diagnosed with renal cell carcinoma or pheochromocitoma from January 2000 until May 2009 (age at diagnosis <18 years) and registered in the TREP, alive, with or without disease, were considered for this study. These patients were registered at 18 reference Italian Pediatric Surgery or Oncology centers.
Patients were contacted by the Reference Center in order to obtain blood DNA to detect germ-line mutation of the following genes:
VHL (Von Hippel-Lindau disease): in renal cell carcinomas and pheochromocytomas
RET (MEN2), SDHB, SDHC, SDHD (Hereditary Paraganglioma-Pheochromocytoma Syndrome): in pheochromocytomas only.
For patients with renal cell carcinoma, referring clinicians were asked to complete a questionnaire, aimed to enlighten the presence of signs and symptoms suggestive of the possible associated syndromes.
Mutation scanning of the VHL gene for identification of point or small size mutations was conducted on the entire coding sequence and intron-exon boundaries, by PCR amplification, DHPLC and direct sequence analysis. Quantitative Real Time PCR for the identification of deletions of part or the entire gene, was performed on genomic DNA fragments representing each VHL exon.
Genetic analysis of RET, SDHB, SDHC, SDHD genes was conducted by direct sequencing of coding sequence and intron-exon boundaries. For RET gene, exons 8, 10, 11, 13, 15 and 16 were sequenced. For SDHx genes, all 8 SDHB exons, all 6 SDHC and 4 SDHD exons were entirely sequenced. Rearrangement analysis was conducted by MLPA (Multiple Ligation Probe Assay).
Finally we analyzed clinical data in relation to the presence of genetic syndromes.
RESULTS
Genetic analysis was performed in 13 on 32 eligible patients with renal cell carcinoma. In all cases no mutation were found. In no case the questionnaire, completed in 11 patients, suggested the presence of an underlying genetic syndrome.
14 patients with pheochromocytoma (on 20 eligible) underwent the genetic analysis: we found a germ-line mutation in 7 (2 VHL, 1 SDHD, 4 SDHB) with an overall prevalence of 50%. When possible, genetic analysis was extended to family members: until now we found 9 mutations in SDHB gene and 1 mutation of SDHD.
From a clinical point of view our data support the role of a complete surgery of the tumor. Patients with genetic syndrome did not significantly differ from nonsyndromic ones in terms of clinical manifestations and prognosis.
CONCLUSIONS
As far as renal cell carcinoma is concerned, the limited number of cases analyzed until today does not allow to draw any significant conclusion. Particularly, we could not detect an association with VHL disease.
We found an high prevalence (50%) of genetic disorders associated with pheochromocytoma otherwise labeled "sporadics". This prevalence is higher than what reported in adulthood, confirming that the incidence of pheochromocytoma in pediatric age is more frequently associated to an inherited disorder.
Our data show that some rare tumors in pediatric age can be the first manifestation of a genetic syndrome. Both renal cell carcinoma and pheochromocytoma clinical outcome strictly depend on completeness of surgery; however these patients need to be considered also from a genetic point of view for the possible implication that a family cancer syndrome can have for the patient and other family members.Consideriamo "tumori rari in età pediatrica" quei tumori con un incidenza inferiore ai 2 casi/1.000.000 bambini/anno e che non sono inclusi in protocolli di trattamento dell'Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP). Questi Tumori sono l'oggetto di un progetto nazionale denominato Progetto TREP che si propone fra gli obiettivi la registrazione dei pazienti con tumore raro e l'avvio di studi a loro dedicati. Questo studio si basa sull'ipotesi che l'insorgenza in un bambino di un tumore tipico dell'età adulta, ma estremamente raro in età pediatrica possa essere l'espressione di una condizione genetica predisponente. Infatti più è precoce l'età di insorgenza di un tumore meno è facile che sia avvenuta un' esposizione a fattori ambientali. Il carcinoma renale (CR) può presentarsi in forma sporadica o come parte del quadro clinico di alcune malattie genetiche, tra cui la malattia di Von Hippel-Lindau. Analogamente feocromocitoma e paraganglioma possono presentarsi sia in forma sporadica che associati ad alcune malattie geneticamente trasmissibili tra cui la malattia di Von Hippel-Lindau, la sindrome del feocromocitoma/paraganglioma ereditario, la sindrome da neoplasie endocrine multiple tipo 2 (MEN 2) e la neurofibromatosi tipo 1. SCOPO Nella tesi riportiamo i dati preliminari di uno studio retrospettivo e prospettico condotto nell'ambito del Progetto TREP, che ha lo scopo di valutare la prevalenza delle principali sindromi genetiche associate a carcinoma renale e a feocromocitoma in età pediatrica. MATERIALI E METODI Sono stati considerati i pazienti con carcinoma renale e con feocromocitoma registrati nel Progetto TREP di età <18 anni, con diagnosi da gennaio 2000 a maggio 2009 e vivi, con o senza evidenza di malattia, al momento dello svolgimento di questo studio. Questi pazienti sono stati registrati da 18 Centri italiani di Chirurgia o Oncologia Pediatrica. I pazienti, sono stati ricontattati dal medico del centro di riferimento e gli è stato proposto di essere sottoposti a prelievo di sangue periferico per ricerca di alterazioni genetiche. In particolare sono state ricercate: VHL (malattia di Von Hippel-Lindau): sia per i carcinomi renali che per i feocromocitomi RET (MEN2), SDHB, SDHC e SDHD (sindrome del feocromocitoma/paraganglioma familiare): solo per i feocromocitomi. Inoltre per i carcinomi renali è stato compilato dal clinico che aveva in cura il paziente un questionario che cercava di identificare sintomi e segni delle possibili sindromi associate. L'analisi delle mutazioni del gene VHL per l'identificazione di mutazioni puntiformi o di piccola taglia è stata condotta sull'intera sequenza codificante e sulle zone di giunzione introne-esone attraverso amplificazione in PCR, DHPLC e sequenziamento diretto. La PCR Real Time quantitativa è stata utilizzata su frammenti di DNA genomico rappresentanti ogni esone del gene VHL per identificare delezioni di parti o dell'intero gene. L'analisi genetica del gene RET e dei geni SDHB, SDHC ed SDHD è stata condotta mediante sequenziamento diretto delle regioni codificanti e delle regioni introniche fiancheggianti. Per il gene RET sono stati sequenziali gli esoni 8, 10, 11, 13, 15 e 16. Per quanto riguarda i geni SDHx sono stati sequenziati interamente gli 8 esoni di SDHB, i 6 di SDHC e i 4 di SDHD; inoltre è stata condotta l'analisi dei riarrangiamenti mediante MLPA (Multiple Ligation Probe Assay). Abbiamo infine analizzato i risultati del trattamento correlandoli alla presenza di una sindrome genetica. RISULTATI Per quanto riguarda i carcinomi renali sono stati identificati 32 pazienti eligibili al nostro studio. La scheda anamnestica è stata somministrata in 11 pazienti, e non ha posto in nessun paziente il sospetto clinico di una sindrome genetica associata. L'analisi genetica per VHL è stata condotta in 13 pazienti ed in tutti i casi ha dato esito negativo. Clinicamente la prognosi è apparsa correlata con lo stadio e quindi con la chirurgia: i pazienti con tumore localizzato asportato completamente hanno mostrato un' ottima sopravvivenza. Per i feocromocitomi l'analisi genetica è stata condotta in 14 pazienti su 20 eligibili ed ha evidenziato una mutazione germinale in 7 (2 VHL, 1 SDHD, 4 SDHB) con una prevalenza totale del 50%. Ove possibile l'analisi genetica è stata estesa anche ai familiari: finora sono stati identificati 9 familiari con mutazione del gene SDHB e uno con mutazione di SDHD. Dal punto di vista clinico i nostri dati confermano l'importanza di una chirurgia completa del tumore. Non è stata riscontrata una differenza significativa nelle manifestazioni cliniche e nella prognosi dei pazienti sindormici quando confrontati a quelli non sindormici. CONCLUSIONI Per quanto riguarda il carcinoma renale, non siamo riusciti ad evidenziare una associazione con la sindrome di VHL, ma la limitata numerosità del campione esaminato ci permette di trarre solo delle conclusioni preliminari. Nei feocromocitomi abbiamo riscontrato un' elevata prevalenza (50%) di sindromi genetiche associate. Tale frequenza è superiore rispetto a quanto riportato in casistiche di pazienti adulti confermando che l'insorgenza di un feocromocitoma in età pediatrica è maggiormente associata ad una sindrome genetica. I nostri dati dimostrano che alcuni tumori rari per l'età pediatrica possono rappresentare la prima manifestazione di una sindrome genetica. Il risultato del trattamento è strettamente correlato all' esito della chirurgia sia per i carcinomi renali che per il feocromocitoma. E' però importante sottolineare che oltre le problematiche inerenti al trattamento vanno considerate quelle di tipo genetico per le implicazioni che una family cancer syndrome può avere per la famiglia e il paziente stesso.
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Mallet, Dominique. « Interet du tumor necrosis factor alpha dans le suivi precoce des transplantations renales ». Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX20913.
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Suzigan, Sueli. « Angiogênese em neoplasias epiteliais corticais renais : estudo de 41 casos ». Faculdade de Medicina de São José do Rio Preto, 2002. http://bdtd.famerp.br/handle/tede/43.
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Previous issue date: 2002-05-03Introduction. Tumor growth and metastasis depend greatly on angiogenesis. There are several angiogenic growth factors able to induce new vessels in renal tumors, but the most important are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). The aim of our study was to investigate expression of b-FGF and to quantify microvessel density (MVD) in oncocytomas and renal cell carcinomas (RCCs) and to relate these parameters of tumor vascularity to other clinicopathological features. Material and Methods. b-FGF and CD31 immunostaining were performed on formalin-fixed paraffin-embedded archival tissues from Larpac Laboratories files, including 36 RCCs (10 conventional, 10 papillary, 8 sarcomatoid, and 8 chromophobe) and 5 oncocytomas. Angiogenesis was quantified microscopically by two independent observers. Results. b-FGF was positive in all five oncocytomas and only in seven of 36 RCCs: 5 of conventional type, 1 papillary, and 1 chromophobe. All sarcomatoid carcinomas were negative. The expression of b-FGF was not related to tumor size, grade, stage, or short survival in either group. MVD mean value was 124.16 ± 50.1 in oncocytomas and 91.54 ± 52.4 in RCCs. The pattern of vascularization observed in oncocytomas was characterized by a fine vascular network around groups of tumor cells although in RCCs the microvessels tended to be more disorganized. When analyzing only carcinomas, patients who died within 12 months after the diagnosis had a tumoral MVD mean value significantly higher (124.12 ± 75.2) than that observed in patients who were still alive one year after diagnosis (80.34 ± 37.8). ix Conclusion. We demonstrate that b-FGF is expressed more often in oncocytomas than in RCCs but MVD is similar in both groups of tumors. The high expression of b-FGF in oncocytomas may reflect the peculiar pattern of vascularization of these tumors. High MVD in rapidly lethal RCCs is an indication that angiogenesis may be correlated with the degree of malignancy of these tumors.
O desenvolvimento dos tumores e das suas metastases dependem em grande parte da angiogenese tumoral. Existem varios fatores de crescimento capazes de induzir à neoformação vascular nas neoplasias renais, porém, os mais importantes são o fator de crescimento do entotélio vascular (vegf) e o fator de crescimento fibroblástico básico (bfgf). O objetivo deste estudo foi o de investigar a expressão do b-fgf e a densidade microvascular (dmv) nos oncocitomas e nos carcinomas de células renais (ccrs) e correlacionar estes parâmetros da vascularização tumoral com outros ascpectos clínico-patológicos. Material e métodos. O estudo imunohidtoquímico para o b-fgf e o cd31 (densidade microvascular) foi realizado em material fixado em formalina e incluído em parafina de 36 casos de ccrs (10 convencionais, 10 papilíferos, 8 sarcomatóides e 8 cromófobos) e 5 oncocitomas, oriundos de exames anátomo-patológicos por dois observadpres independentes. Resultados. Nota de Resumo Foi encontrada positividade para o b-fgf em todos os 5 casos de oncocitomas e em 7 dos 36 casos de ccrs: 5 do tipo convencional, um papilífero, e um cromófobo. Todos os carcinomas sarcomatóides mostraram-se negativos. A expressão tumoral do b-fgf não apresentou correlação com tamanho tumora, grau histológico, estadio patológico, ou sobrevida a curto prazo em nenhum dos grupos. O valor médio da dvm foi de 124,16 +/- 50,1 nos oncocitomas e de 91,54 +/- 52,4 nos ccrs. O padrão de vascularização observado nos oncocitomas era caracterizado por um delicado leito vascular envolvendo grupos de celulas tumorais, enquanto que nos ccrs a microvascularização se apresentou de forma mais organizada. Entre os carcinomas, os tumores que se mostraram letais nos 12 primeiros meses após o diagnóstico, apresentaram um ídice angiogênico significativamente maior (124,12 +/- 75,2) em relação aos pacientes que ainda permaneciam vivos um ano após o diagnóstico (80,34 +/- 37,8). Conclusão. Demostramos que o b-fgf está expresso mais freqüentemente nos oncocitomas do que nos ccrs. Nota de Resumo Apesar de as dmv ser semelhante em ambos os grupos tumorais, observou-se um padrão de vascularização característico nos oncocitomas. Uma dvm mais elevada nos ccrs, rapidamente letais é indicativo de que a angiogenese possa estar correlacionada com grau de malignidade destes tumores.
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Hellström, Vivan. « The clinical perspective on malignancies in renal transplanted patients ». Doctoral thesis, Uppsala universitet, Transplantationskirurgi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282131.
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Post-transplant malignancies cause significant morbidity and mortality. In this thesis we investigated malignancies in renal transplanted patients from a clinical viewpoint. The use of regional tumour registries considerably improved identification of pre- and post-transplant malignancies, which are generally underreported in transplant registries. Despite previously adequate cancer treatments with favourable prognosis, patients with pre-transplant malignancies showed higher incidence of post-transplant cancer and reduced survival compared to a 1:3 ratio matched control group of patients without a previous cancer from the Collaborative Transplant Study in Europe. A careful oncological surveillance pre-transplant and post-transplant is recommended. A multidisciplinary team evaluated the immunosuppressive and oncological treatment in a clinical prospective observational study of 120 renal transplanted patients with post-transplant malignancies. In two-thirds of the patients immunosuppression was possible to change to mTOR inhibitors with anti-tumour effects. Oncological treatment was adjusted in 50% of patients with solid or haematological tumours. MDT assessments are essential for optimizing treatment of post-transplant malignancies. Number of previous cutaneous squamous cell carcinoma (SCC) posed the most significant risk variable in predicting subsequent SCCs during a two-years study of 73 transplanted patients with at least one SCC. Incidence of transplant-derived tumours is 5 times higher than anticipated. Three of eleven cancers in urinary tract and two of four cancers in the transplants were transplant-derived. Five of eleven cancers of the urinary tract were BK-virus positive. Allograft immune response against these tumours offer new options for cancer treatment such as immunomodulatory or anti-viral treatment in combination with modified immunosuppression.
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Heiz, Monika. « Growth control and L1-CAM phosphorylation in renal tumor cells diploma work / ». Zürich : ETH, Eidgenössische Technische Hochschule Zürich, Departement Angewandte Biowissenschaften, Institut für Pharmazeutische Wissenschaften, 2000. http://e-collection.ethbib.ethz.ch/show?type=dipl&nr=14.
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Queiroz, Marcus Vinicius Baptista. « Ablação percutânea do parênquima renal por radiofrequência ». Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5153/tde-04082011-155239/.
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INTRODUÇÃO: Os tumores renais pequenos e localizados são hoje diagnosticados mais frequentemente graças ao uso mais intenso dos métodos de imagem, o que favorece técnicas de tratamento menos traumáticas e igualmente eficazes. Dentre as técnicas minimamente invasivas, uma alternativa atraente é a radiofrequência (RF) por ser eficiente, de baixo custo e fácil aplicação. OBJETIVO: Avaliar métodos de aprimoramento da aplicação da RF para promover lesão celular renal de forma mais eficiente, obtendo lesões maiores, utilizando diferentes temperaturas e, em seguida, administrar drogas vasoativas para comparar o tamanho das lesões. Objetivou-se avaliar também se há remanescência de células viáveis na área abrangida pela lesão. MATERIAL E MÉTODO: O estudo foi realizado na Divisão de Clínica Urológica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre janeiro de 2005 e dezembro de 2008. Inicialmente, 16 cães (Grupo A) foram submetidos a RF no parênquima renal com diferentes temperaturas: 80, 90 e 100 graus centígrados. Para comparar os resultados, foi analisado o tamanho das lesões nas diferentes temperaturas por medida da profundidade e da largura, correlacionadas com a impedância. Em seguida, usando a temperatura de 90 oC, 14 cães foram submetidos a RF com injeção dos dois diferentes agentes vasoativos: como vasoconstritor, a adrenalina (Grupo B), versus a prostaglandina E1 (Grupo C) como vasodilatador. Após 14 dias, os animais foram submetidos a nefrectomia para avaliação das lesões e a sacrifício. RESULTADOS: Houve diferença estatisticamente significante na profundidade (p < 0,001) e largura (p < 0,001) da lesão entre as três temperaturas (80, 90 e 100 oC), sendo que há um pico no tamanho das lesões renais na temperatura de 90 oC. Foi observada diferença estatisticamente significante da impedância entre as três temperaturas estudadas (p < 0,001), e se observou resultado mais favorável a 90 oC (menor impedância) e similar entre as temperaturas de 80 e 100 oC. A segunda etapa do estudo demonstrou que o uso da prostaglandina E1 resultou em lesões significativamente mais profundas e mais largas que o uso da adrenalina e também que a resistência tecidual foi menor com a prostaglandina E1. CONCLUSÕES: A temperatura de 90 oC foi mais eficiente para provocar destruição celular com a RF por produzir lesões mais extensas na largura e profundidade, quando comparada com as temperaturas de 80o e 100 oC (p < 0,001). A impedância também foi menor com 90 oC (p < 0,001). Observou-se que as lesões produzidas sem drogas não apresentaram diferença significante comparado com o uso de prostaglandina E1. Porém, o uso de adrenalina promoveu lesões menores (p < 0,001) quando comparada com os dois outros grupos. Não foram observadas células viáveis na análise microscópica dentro dos limites atingidos pela RF em ambos os experimentosINTRODUCTION: Small, localized renal tumors are diagnosed more frequently nowadays due to the more intense use of imaging methods, which favor less traumatic but equally efficacious treatment techniques. Among the minimally invasive techniques, an attractive alternative is that of radiofrequency (RF), as it is efficient, and easily applicable. OBJECTIVE: To assess methods for the improvement of the application of RF, for the more efficient promotion of the renal cell lesion, to obtain larger lesions, making use of various temperatures and then administering vasoactive drugs to compare the size of the lesions produced, and also to assess the existence of remaining viable cells in the area affected by the lesion. MATERIAL AND METHOD: The study was undertaken at the Urological Clinical Division of the Hospital das Clínicas of the Medical School of the University of São Paulo, between January 2005 and December 2008. Initially, 16 dogs (Group A) underwent RF of the renal parenchyma at various temperatures: 80, 90 and 100 degrees centigrade. For the comparison of the results, the size of the lesions at the various temperatures was analyzed by the measurement of their depth and width, correlated with the impedance. Then, using a temperature of 90 oC, 14 dogs were submitted to RF with an injection of one of the two different vasoactive agents: adrenaline, vasoconstrictor (Group B), versus with E1 prostaglandin, vasodilator (Group C). After 14 days, the animals underwent nephrectomy for the assessment of the lesions, and then were sacrificed. RESULTS: It was observed that, with the application of RF at the temperatures of 80, 90 and 100 oC, there was a statistically significant difference in the depth (p < 0.001) and width (p < 0.001) of the lesions as between the three temperatures, with a peak in the size of the renal lesions at 90 oC. A statistically significant difference in impedance was observed as between the three temperatures studied (p < 0.001), the most favorable result occurring at 90 oC (least impedance) and similar ones occurring between the temperatures of 80 and 100 oC. The second phase of the study demonstrated that the use of the prostaglandin E1 gave rise to significantly deeper and wider lesions than did the use of adrenaline and also that the tissue resistance was less than with the prostaglandin E1. CONCLUSIONS: It was observed that the temperature of 90oC was more efficient in provoking cell destruction with RF as it produced more extensive lesions both in width and depth than those at the temperatures of 80o and 100 oC (p < 0.001). The impedance was also less at 90 oC (p < 0.001). It was observed that the lesions produced without drugs presented no significant difference with the use of prostaglandin. However, the use of adrenaline provoked smaller lesions (p < 0.001) than did the other two (technical) groups. No viable cells were observed by microscopic analysis within the limits attained by the RF, in either of the experiments
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Ogawa, Osamu. « Molecular Genetic Analysis of Human Renal Tumors by Using Restriction Fragment Length Polymorphisms ». Kyoto University, 1994. http://hdl.handle.net/2433/160715.
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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものであるKyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第5794号
医博第1587号
新制||医||590(附属図書館)
UT51-94-R318
京都大学大学院医学研究科外科系専攻
(主査)教授 野田 亮, 教授 佐々木 正夫, 教授 吉田 修
学位規則第4条第1項該当
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Meadows, Susan Dove. « PERSISTENT NEPHROTOXICITY AND RENAL TUMOR PROMOTION IN SWISS-WEBSTER MICE FOLLOWING EXPOSURE TO 1,2-DICHLOROVINYLCYSTEINE (KIDNEY, CANCER) ». Thesis, The University of Arizona, 1985. http://hdl.handle.net/10150/275292.
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Wilkins, Danice E. C. « CD40 stimulation induces chemokine production and anti-tumor effects in renal cell carcinoma ». abstract and full text PDF (free order & ; download UNR users only), 2007. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1442869.
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Gutteridge, Robert. « Caveolin-1 is a modulator of clonogenicity in renal cell carcinoma ». Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/91911/.
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Renal cell carcinoma (RCC) represents a group of aggressive tumours of the kidney. These tumours have a high propensity for metastasis and are extremely treatment refractive after disease relapse. Therefore, the identification of new therapeutic targets is of great importance. One such potential target for therapy are cancer stem cells (CSCs). CSCs are populations of cells imbued with a stem cell-like phenotype capable of driving tumour formation, metastasis and chemoresistance. As such, reliable methods for the identification of CSC populations and defining targets important to their functionality, in hopes of developing more potent therapeutics is of great importance. Previous work has found CAV1 to play a significant role in the malignant progression of RCC and also in the maintenance of adult stem cell populations. As such, this work aimed to understand if common markers of CSC phenotype in combination with CAV1 can act indicators of poor prognostic outcome in clinically confined RCC. Furthermore, this work sought to identify CSC populations from RCC cell lines using a panel of surface markers common to embryonic, mesenchymal and cancer stem cells. Then, understand if CAV1 is responsible for driving the CSC phenotype in these CSC populations by regulating one of the major characteristics of CSC biology, self-renewal. Co-expression of CD44 and CAV1 in RCC tumours indicated greatly reduced disease free survival in clinically confined RCC. Additionally, CD44/CAV1 was found to be the most significant covariate in predicting disease recurrence. In vitro analysis, using a panel of CSC related markers, was unable of identifying a putative CSC population. However, CAV1 expression in the VHL positive CAKI-1 cell line was important for the maintenance of clonogenicity. Incubation of CAV1 deficient CAKI-1 cells under hypoxic conditions was able to restore lost clonogenicity. Further iv work revealed that CAV1 maintains clonogenicity in CAKI-1 through activation of STAT3 and -catenin. This suggests an important role for CAV1 in the maintenance of clonogenicity through STAT3 activation in VHL competent RCC.
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Vieira, Joana Virgínia Pinto Valejo de Magalhães. « Diagnóstico diferencial de tumores renais por análise genómica de biópsias aspirativas ». Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/7226.
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Vieira, Joana Virgínia Pinto Valejo de Magalhães. « Diagnóstico diferencial de tumores renais por análise genómica de biópsias aspirativas ». Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/7226.
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Li, Tak-kin, et 李德健. « A study of Twist and DJ-1 expressions and their clinical significance in renal cell carcinoma of clear cell type ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45153863.
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Nahorski, Michael Stefan. « Investigation into the molecular mechanisms of inherited renal cancer ». Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3663/.
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Birt Hogg Dubé (BHD) syndrome is an inherited cancer susceptibility syndrome characterised by the development of fibrofolliculomas on the face and upper torso, and increased risk of lung cysts, spontaneous pneumothorax and renal cancer. The findings presented in this thesis advance knowledge into how the mutations in the FLCN gene cause the phenotypes associated with BHD syndrome, and provides novel insights into the functions of folliculin within the cell. The results presented provide further evidence of the association between BHD syndrome and increased risk of colorectal cancer in a subset of BHD syndrome families, and suggest that this association appears restricted to those patients with an exon 11 mononucleotide tract mutation. Evolutionary conservation analysis across the FLCN sequence suggests that pathogenic mutations could be expected throughout the gene, and identifies a region between codons 100-230 of increased evolutionary significance. The experiments undertaken demonstrate a practical strategy for determining the pathogenicity of non-truncating folliculin variants in vitro, and indicate that loss of protein stability is the main mechanism of pathogenicity for the previously reported non-truncating mutations within FLCN. Finally, this thesis reports the first identification of p0071 as a folliculin interacting protein. Folliculin deficiency exerts a functional impact on previously reported p0071 functions inducing RhoA signalling upregulation, mitotic defects and disruption of cell junctions. These results demonstrate the potential efficacy of using inhibitors downstream of RhoA as therapeutic targets in BHD tumours with dyregulated RhoA signaling, and provide novel directions for research into BHD syndrome.
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Lawrentschuk, Nathan Leo. « Hypoxia and angiogenesis in renal cell carcinoma ». Connect to thesis, 2009. http://repository.unimelb.edu.au/10187/6790.
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Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans.Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16
Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated.
Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17
Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18
Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.
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Splittstößer, Vera [Verfasser]. « Expressionsmuster des Apoptoseproteins Programmed Cell Death Protein 4 (Pdcd4) in urologischen Tumoren / Vera Renate Splittstößer ». Bonn : Universitäts- und Landesbibliothek Bonn, 2014. http://d-nb.info/1238687202/34.
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O'Flaherty, Linda H. « Development of novel in vitro and in vivo models for determining primary events in HLRCC tumourigenesis ». Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.565984.
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Development of novel ill vitro and ill vivo models for determining primary events in HLRCC tumourigenesis Linda O'Flaherty, Mansfield College Thesis submitted for degree of Doctor of Philosophy Nuffield Department of Clinical Medicine, University of Oxford Hilary Term 2012 Germline mutations of fumarate hydratase (FR), encoding an enzyme of the tricarboxylic acid (TCA) cycle, predispose affected individuals to hereditary leiomyomatosis and renal cell cancer (HLRCC). FH-deficient cells and tissues have been shown to accumulate fumarate, exhibit S-(2-succinyl) cysteine (2SC) protein modifications and to constitutively express hypoxia-inducible factor alpha (HIF -1 a and -20.), under nonnoxic conditions. This thesis presents a phenotypic characterisation of FhI-I- mouse embryonic fibroblasts (MEFs), generated from previously reported conditional Fhl knockout mice, as a new in vitro system for investigating and identifying biochemical and metabolic pathways that are dysregulated as a result of FhI inactivation. These cell lines reproduced the aforementioned phenotypes, in addition to an observed shift from oxidative phosphorylation (OXPHOS) to glycolytic metabolism. Re-expression of either full length, mitochondrial-targeted FH (FhI-I- +FH) or cytoplasmic FH (Fhrl- +FHl'1MTS) in FhI-deficient MEFs was sufficient to reduce intracellular fumarate and to correct for the dysregulation of the Hif pathway. These results were of particular interest as they demonstrated that nonnoxic stabilisation of Hif-Ia occurs independently of the persistent mitochondrial defect observed in Fhrl- +FHl'1MTS MEFs. These findings were corroborated in vivo following the development of transgenic mouse models, ubiquitously expressing either FH or FHl'1MTS in mice with targeted inactivation of FhI in renal tubular cells. Surprisingly, the cytoplasmic-restricted FH (FHl'1MTS) transgene was just as efficient as the transgenic mice expressing mitochondrial- targeted FH at rescuing the cystic phenotype associated with Fh I-deficiency in the kidneys. As the function of cytoplasmic FH has remained poorly understood, these results go some way to extricating a role for this isofonn of FH. The results of this thesis demonstrate that these novel in vitro and in vivo models, used either alone or in combination, are a versatile and robust paradigm for studying altered cell metabolism in not only HLRCC but other diseases associated with metabolic dysregulation.
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Scalera, Giovanni Battista. « Risonanza Magnetica Dinamica e TC multifasica nella caratterizzazione dei tumori renali di piccole dimensioni (<3cm) ». Doctoral thesis, Università di Catania, 2012. http://hdl.handle.net/10761/1112.
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Allo stato attuale RM dinamica e TC multifasica mediante l analisi dell enhancement consentono informazioni quali- quantitative della vascolarizzazione di piccoli tumori renali e quindi una più accurata caratterizzazione.
TIPOLOGIA DELLO STUDIO ED OBIETTIVI
Studio retrospettivo di piccole masse renali con diagnosi istologica, identificate con ecografia e/o con TC trifasica.
OBIETTIVO PRIMARIO:
Confrontare i risultati della RM dinamica e della TC trifasica nella valutazione quali- quantitativa dell enhacement dei carcinomi renali di piccole dimesioni.
OBIETTIVO SECONDARIO:
Valutare la possibilità dell analisi quali- quantitativa dell enhancement con RM dinamica e TC trifasica nella diagnosi differenziale dei tumori renali.
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CAZZANIGA, MARTA. « Ricerca di una firma molecolare tipizzante tumori renali mediante approccio proteomico di profiling in spettrometria di massa ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/104019.
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Renal cell carcinoma accounts for about 85% of primary kidney tumors and its incidence worldwide is increasing rapidly. Although the diagnosis of RCC is routinely performed by means of multiple imaging techniques, benign solid renal masses sometimes cannot be confidently differentiated from malignant ones. Moreover, the TNM (Tumor-Node-Metastasis) classification system, the Fuhrman grading system and serum markers are still the main factors used to predict the outcome of patients. For these reasons, RCC still remains a significant clinical challenge not only in terms of early diagnosis but also clinical management. Moreover, since the main alterations in regulation processes caused by tumorigesis not only involve genes but also proteins, MS-based protein profiling is considered an effective approach both for the discovery of multiple biomarkers and for the detection of disease specific modifications. Therefore, this PhD project has been focused on the study and characterisation of the urinary peptidome and proteome of RCC patients, patients affected by other kidney neoplasms and control subjects in order to evaluate potential molecular signatures capable of characterising renal cancers. For this purpose, sistematic analysis at the peptidome level employing a protein profiling approach based on MALDI-TOF mass spectrometry analysis combined with pre-purification step of urine samples using functionalized magnetic beads, has been performed. This technique has allowed, on one hand, to build models of potential biomarkers able to discriminate not only ccRCC patients from controls, but also to significantly distinguish malignant renal masses from benign forms and, on the other hand, to highlight alterations of endogenous peptides according to clinical data (stage, grade, dimension). The identification of discriminant and/or tumor progression related signals has been obtained through a nLC-ESI MS/MS approach on urine pools of 80 healthy volunteers and 80 RCC patients. For the proteomic analysis, a tryptic digestion of urine samples using the FASP (Filter Aided Sample Preparation) protocol followed by shotgun analysis by nanoUHPLC-ESI MS/MS has been performed. The relative label-free quantification has facilitated the investigation of protein alterations in ccRCC subjects. The subsequent functional analysis has highlighted the bological processes and the molecular functions in which the varied proteins are involved.
Moreover, in the study of a complex system such as the kidney, a systematic comparison between different –omic sciences (peptidomics/proteomics) could highlight functions, biological processes and molecular targets that are implicated in the deregulation caused by the presence of the tumor and for this reason an integration of the collected data has been performed in order to identify potential targets and biological effectors that could improve the understanding of the intricate and multifactorial mechanisms underlying kidney malignancies.
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Oldham, Kimberley Anne. « The recruitment and role of effector and regulatory T cells in renal cell carcinoma ». Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3263/.
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Immunotherapy for renal cell carcinoma (RCC) has yielded some clinical responses. However this approach frequently fails, possibly due to inefficient migration of T-cells to tumour tissue or immunosuppressive mechanisms within the tumour environment. To aid development of T-cell therapy for RCC I investigated how T-cells are recruited to this tumour, which T-cell subsets infiltrate, and how they function. Analysis of the expression of all 19 chemokine receptors on matched TIL and PBMC demonstrated that CCR5, CXCR3 and CXCR6 were expressed at significantly higher levels on tumour-infiltrating T-cells than memory T-cells in PBMC, suggesting a role for these receptors in recruitment to RCC. Immunohistochemistry showed the corresponding ligands were present in RCC, and transwell assays confirmed the ligands induce migration of TIL. I demonstrated Foxp3\(^+\)CD25\(^{hi}\)CD127\(^{low}\) Tregs were enriched within the tumour, and also expressed high levels of CCR5, CXCR3 and CXCR6, as well as CCR6. They lacked expression of IL-2 and IFN-\(\gamma\) post-stimulation, consistent with a regulatory phenotype. Functional characterisation of Foxp3\(^-\) TIL demonstrated they can function ex vivo, however their high expression of the inhibitory molecule PD-1 may indicate exhaustion in vivo. Double positive CD4\(^+\)CD8\(^+\) T-cells were also enriched in TIL and had a similar functional profile to CD8 T-cells.
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Brito, Glauber da Costa de. « Análise da expressão de RNAs intrônicos não-codificadores em carcinomas de célula renal ». Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-07022008-100457/.
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O carcinoma de célula renal (CCR) subtipo célula clara é o câncer mais letal e prevalente do sistema urinário. A transformação maligna no CCR está possivelmente associada à mudanças no perfil de expressão de oncogenes e genes supressores de tumor, e acredita-se que estas alterações sejam críticas para o desenvolvimento do fenótipo maligno. Para identificar novos genes e vias moleculares associadas à transformação maligna no CCR célula clara, foram analisados perfis de expressão gênica de amostras pareadas de tumor e tecido não tumoral adjacente de 6 pacientes. Foi utilizada uma plataforma de microarrays de cDNA contendo 2.292 sondas mapeando éxons de genes codificadores e 822 sondas de RNAs não-codificadores mapeando em regiões intrônicas. A transcrição intrônica foi detectada em todos os tecidos normais e neoplásicos. Utilizando uma combinação de dois testes estatísticos e uma validação por leave-one-out, foi selecionado um subconjunto de 64 transcritos com expressão significativamente alterada em CCR célula clara em relação ao tecido não tumoral adjacente, estando a maior parte (86%) com expressão diminuída em CCR. Entre os transcritos com expressão diminuída, 49 mapearam em regiões não-traduzidas ou éxons de genes codificadores e 6 mapearam em regiões intrônicas de genes codificadores conhecidos. Os níveis de expressão diminuída de SIN3B, TRIP3, SYNJ2BP e NDE1 (p < 0,02), e de transcritos intrônicos derivados dos loci de SND1 e ACTN4 (p < 0,05), foram confirmados em CCR célula clara por Real-time RT-PCR. Um subconjunto de 25 transcritos se mostrou alterado em 6 amostras adicionais de CCR não célula clara, indicando alterações transcricionais comuns em CCR independentemente do subtipo histológico ou do estado de diferenciação do tumor. Além disso, foi analisado o perfil de metilação dos genes com expressão diminuída em tumor SIN3B, TRIP3, SYNJ2BP e GPX3. Nossos resultados indicam um novo conjunto de candidatos a gene supressor de tumor, que 8 podem desempenhar um papel importante na transformação maligna de células renais normais.The clear cell subtype of renal cell carcinoma (RCC) is the most lethal and prevalent cancer of the urinary system. The carcinogenesis in RCC is thought to be associated with changes in the expression of several genes, and this alteration in gene expression is believed to be critical to the development of the malignant phenotype. To investigate new genes and molecular pathways associated with malignant transformation in clear cell RCC, gene expression profiles of matched samples of tumor and adjacent non-neoplastic tissue obtained from 6 patients were analysed. A custom-built cDNA microarray platform was used, comprising 2,292 probes that map to exons of genes and 822 probes for noncoding RNAs mapping to intronic regions. Intronic transcription was detected in all normal and neoplastic renal tissues. A subset of 64 transcripts with levels significantly deregulated in clear cell RCC relative to the matched non-tumor tissue, mostly (86%) downregulated in CCR, was
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Ferreira, Adilson Kleber. « Alquil fosfatado sintético precursor dos fosfolipídios da membrana celular com potencial efeito antitumoral e apoptótico em modelos de tumores experimentais ». Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-20052013-145336/.
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Neste estudo foram avaliados os efeitos antitumorais da fosfoetanolamina sintética (FS) em modelos de tumores experimentais e as vias de sinalizações envolvidas nesta atividade. In vitro a FS foi citotóxica para as linhagens de células tumorais de melanoma humano, SK-MEL-28, carcinoma renal murino RENCA e para as células do carcinoma de pulmão de não pequenas células NSCLC. Alterações ultraestruturais como a condensação da cromatina, formação de blubes de membranas e mitocôndrias eletrodensas foi acompanhada pela redução do potencial elétrico mitocondrial. Aumento da ativação da caspase 3 e 8 e da expressão da proteína Bax, além da redução da CDK9 e CDK4/6, também foram observados. A redução da migração e proliferação das células endoteliais HUVEC induzida pela FS foi associada com a modulação da expressão do VEGF-A. resultando na inibição in vitro da formação do tubo endotelial. In vivo a FS foi capaz de inibir o crescimento dos tumores sólidos do melanoma e do carcinoma renal murino de forma superior aos quimioterápicos Dacarbazina (DITC) e ao Sunitinib. No modelo de metástase pulmonar utilizando as células RENCA, a FS reduziu o número de nódulos metastáticos pulmonares e aumentou a taxa de sobrevida dos animais. Os efeitos terapêuticos da FS também foram avaliados no modelo de leucemia promielocítica aguda (LPA) transplantada em camundongos NOD/Scid. O tratamento com a FS reduziu o número de blastos periféricos e infiltrados na medula óssea e nos parênquimas, esplênico e hepático. De forma superior a Daunorrubicina (DA) e ao Ácido all-trans retinóico (ATRA), a FS induziu apoptose nos clones malignos que expressão CD34+, bem como nas células CD117+/Gr-1+. Este conjunto de resultados mostra que a FS é um composto promissor na terapêutica contra neoplasiasIn this study, we evaluated the antitumor effects of synthetic phosphoethanolamine (FS) in an experimental tumor model and the signaling pathways involved in this activity. In vitro, FS was cytotoxic to tumor cell lines of human melanoma, SK- MEL-28, renal carcinoma murine, Renca, and for non-small cell lung cancer, NSCLC. Ultrastructural changes such as chromatin condensation, blubes formation on membranes and electrodense mitochondria were accompanied by a reduction of the mitochondrial electric potential. Increased activation of caspase-3, 8 and Bax protein expression, in addition to a reduction of CDK9 and CDK4/6 levels, was also observed. The reduction of migration and proliferation of endothelial cells, HUVEC, induced by FS was associated with the modulation of VEGF-A-expression, resulting in the in vitro inhibition of tubulogenesis. In vivo, FS was able to inhibit the growth of solid tumors of melanoma and renal carcinoma more potently than Dacarbazine (DITC) and Sunitinib. In the lung metastasis model, using RENCA cells, FS reduced the number of metastatic lung nodules and increased the survival rate of the animals. The therapeutic effects of FS were also evaluated in the model of acute promyelocytic leukemia transplanted in mice NOD/Scid. The treatment with FS reduced the number of peripheral blasts and infiltrates in the blood marrow, splenic and hepatic parenchyma. Fs was more potent than Daunorrubicine (DA) and all-trans retinoic acid (ATRA) in the induction of apoptosis in the malignant clones expressing CD34+ as well as CD117+/Gr-1+ cells. Taken together, theses results show that FS is a promising compound for the therapy against tumors
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Barod, R. « Role of the VHL and PTEN tumour suppressors in clear cell renal carcinoma ». Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1331702/.
Texte intégralRésumé :
Kidney cancer affects over 7000 people each year in the UK and its incidence is rising. The majority of patients with clear cell renal carcinoma (ccRCC), the commonest form, harbour mutations in the VHL tumour suppressor. Experimental studies have shown that VHL inactivation is an early, important step in the development of ccRCC. The main identified function of VHL is the regulation of hypoxia inducible factor (HIF). HIF has 2 main isoforms (HIF-1α and HIF-2α), which act as the master regulator of the cellular response to hypoxia and regulate the transcription of several genes. While loss of VHL function has major effects on cancer related cell behaviour, it is insufficient for ccRCC pathogenesis. Further events are required to promote tumour development. In regard to this, I have investigated 2 main themes in this thesis. First, whether predominant HIF-2α expression, compared to HIF-1α, can be identified in tissue from patients with ccRCC, and whether this provides reliable prognostic information. Second, the effect that loss of another tumour suppressor, PTEN, has in VHL -/- ccRCC cells. I identified regions of predominant HIF-2α expression, with corresponding loss of HIF-1α expression in a subset of tumours from 3 independent series of ccRCC tissue. I found differential expression of HIF targets in some of these tumours, providing direct in vivo evidence of transcriptional selectivity in ccRCC. These tumours showed a trend towards poorer prognosis, but this did not reach statistical significance. In vitro experiments on the effect of PTEN loss in ccRCC cells showed that PTEN suppresses HIF-α2, VEGF and other selected HIF targets. Restoration of PTEN in 786-O cells suppresses cell migration, anchorage independent growth and growth of tumour xenografts in nude mice. Collectively, these results support the hypothesis that after VHL inactivation, further events contribute to ccRCC tumourigenesis. Predominant HIF-2α expression and PTEN inactivation may be examples of these events. Insights provided from this thesis contribute to the understanding of ccRCC pathogenesis, which ultimately might lead to the development of novel therapeutic strategies to treat this disease.
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Zastrow, Stefan, Anh Phuong, Immanuel von Bar, Vladimir Novotny, Oliver W. Hakenberg et Manfred P. Wirth. « Primary Tumor Size in Renal Cell Cancer in Relation to the Occurrence of Synchronous Metastatic Disease ». Karger, 2014. https://tud.qucosa.de/id/qucosa%3A70551.
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Objectives: To investigate the controversially discussed relationship between tumor size and the occurrence of primary synchronous metastatic disease in renal cell cancer (RCC).
Patients and Methods: A consecutive RCC cohort of 2,058 patients (150 primary metastatic) who underwent surgery between 1995 and 2010 was investigated. Rates of synchronous metastases were calculated for stratified groups of tumor size. Uni- and multivariate logistic regression models were calculated for the correlation of tumor size with primary metastatic disease.
Results: The rate of metastatic disease increased with increasing tumor size. Tumor size was significantly correlated with synchronous metastatic disease (p < 0.001, c-index 0.772), but for RCCs ≤ 4 cm in size no significant correlation was found. Regarding tumors ≤ 5 cm in size, the correlation became significant (p = 0.028, c-index 0.621). A multivariate logistic regression model for the prediction of synchronous metastatic disease including tumor size, age and comorbidity yielded a significant c-index of 0.82 and was used to construct a nomogram.
Conclusion: Our data confirm the correlation between tumor size and the rate of synchronous metastatic disease. Small renal tumors <4 cm in size have a low risk of synchronous metastatic disease. The risk becomes significantly associated with tumor size for tumors ≤ 5 cm.
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Schnappinger, Julia [Verfasser], et Elfriede [Akademischer Betreuer] Nößner. « Profiling human tumor infiltrating leukocytes comparing renal cell and hepatocellular carcinoma / Julia Schnappinger ; Betreuer : Elfriede Nößner ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1225682452/34.
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Cohen, Jennifer Diane. « Engagement of Map Kinase and mTOR Signalingn by the TSC-2 Tumor Suppressor in Renal Cancer ». Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195527.
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The tuberous sclerosis-2 (Tsc-2) gene product, tuberin, functions as a renal tumor suppressor. Treatment of Eker (Tsc-2 EK/+) rats and primary renal epithelial cells derived from Tsc-2 EK/+ rats (QTRRE cells) with 2,3,5-tris-(glutathion-S-yl) hydroquinone (TGHQ) results in loss of heterozygosity at the Tsc-2 locus in kidney tumors and QTRRE cells. QTRRE cells are carcinogenic in athymic nude mice. Analysis of kidney tumors formed in Tsc-2 EK/+ + rats following 8-months of TGHQ treatment reveals increases in B-Raf, Raf-1, pERK, cyclin D1, p27Kip1, 4EBP1, p-4EBP1(Thr70), p-4EBP1(Ser65), and p-4EBP1(Thr37/46) protein expression. These data establish the involvement of mTOR and MAPK signaling cascades in tuberin null tumors. Similar increases in 4EBP1 and p4EBP1 are observed in renal tumor QTRRE-xenografts in nude mice. Concomitant with increases in expression of these proteins in TGHQ-induced renal tumors, similar changes are observed in QTRRE cells, which also exhibit high ERK, B-Raf and Raf-1 kinase activity; and increased expression of cyclin D1, p27, p-4EBP1 (Thr70), p-4EBP1 (Ser65), and p-4EBP1 (Thr37/46). Manipulation of the Raf/MEK/ERK kinase cascade in QTRRE cells, with kinase inhibitors and siRNA, indicates that Raf-1/MEK/ERK participates in crosstalk with 4EBP1 to regulate translation of cyclin D1.Cyclin D1 and p27 protein levels are increased in the cytoplasm in our RCC models. In normal HK-2 cells, p27 and cyclin D1 are localized to the nucleus. Due to the instability of the cyclin D1-CDK4 complex, p27 interaction is necessary for cyclin D1-CDK4 complex assembly and stabilization in the nucleus. Manipulation of p27 protein levels in QTRRE cells with phosphodiesterase inhibitors, dibutyryl cAMP, and the proteosome inhibitor MG132, all result in a parallel increase in p27 and cyclin D1. Furthermore, p27 siRNA and sorafenib treatment both cause a decrease in p27 and cyclin D1. Further manipulation of cAMP, Rap1B, and B-Raf proteins, revealed that cAMP/PKA/Rap1B/B-Raf activation and B-Raf//ERK MAPK inhibition both modulate p27 expression and compartmental localization in tuberous sclerosis renal cancer. Phosphodiesterase inhibitors play a role in regulating the expression, degradation, and cytoplasmic localization of p27. Therefore, cytoplasmic p27-cyclin D1 mislocalization and stabilization may have an oncogenic role in the cytosol and play a crucial role in tumor formation.
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Arakaki, Ryuichiro. « CCL2 as a potential therapeutic target for clear cell renal cell carcinoma ». 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225490.
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Pettinari, L. « STUDIO DELL'EFFETTO DI UKRAIN SUI MECCANISMI DI TRANSIZIONE EPITELIO-MESENCHIMALE E INVASIVITA' TUMORALE IN CELLULE DI CARCINOMA RENALE ». Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/168385.
Texte intégralRésumé :
Renal cell carcinoma (RCC) is the most common malignancy of the kidney, arising from the cortical tubular epithelium and accounting for 85% of renal cancers. Recent clinical investigations suggested that Ukrain (UK), a semisynthetic derivative of the greater celandine alkaloids, exerts beneficial effects in the treatment of several solid tumors, including the RCC. In this study we investigated whether UK was able to modulate the malignant phenotype of RCC cells, by analyzing the expression of proteins involved in tumor progression.
For this purpose, we investigated whether Ukrain modulates the malignant phenotype of clear cell renal carcinoma (ccRCC) cells Caki-1, Caki-2, ACHN treated with four doses (5, 10, 20, 40 µM) for 24 and 48h. The epithelial-to-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin were analyzed by immunofluorescence, as well as actin and tubulin; matrix metalloproteinase-2 and -9 activity was analyzed by SDS-zymography, intracellular and secreted SPARC protein levels by Western blot, cell cycle by flow cytometry. Ukrain did not induce E-cadherin/β-catenin immunoreactivity at cell-cell boundary, although determined actin cortical expression in Caki-2 and ACHN, and did not affect vimentin organization; however, in some Caki-1 and ACHN cells the perinuclear concentration of vimentin was consistent with its down-regulation. Matrix metalloproteinase-2 and -9 activity was significantly down-regulated 48h after 20 µM Ukrain administration. At this time point Ukrain significantly decreased migration and invasion, and down-regulated SPARC levels in cell supernatants at all doses in Caki-2, and at 20 µM in Caki-1 and ACHN cells, possibly rendering tumor microenvironment less permissive for tumor invasion. Concomitantly, SPARC was up-regulated in all ccRCC cells, suggesting that Ukrain could also affect cell proliferation by cell cycle inhibition, as supported by the cell cycle analysis, since SPARC acts also as cell cycle inhibitor. Our results suggest that Ukrain may switch the EMT-related phenotype of ccRCC cells, and targets the two major aspects involved in RCC progression, such as tumor invasion/microenvironment remodeling and cell proliferation.
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Lima, José de Ribamar Oliveira. « Perfil da cistatina C, interleucina 2, interleucina 6 e fator de necrose tumoral alfa em receptores de transplante renal ». reponame:Repositório Institucional da UnB, 2011. http://repositorio.unb.br/handle/10482/9718.
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O transplante renal é a melhor opção terapêutica e de reabilitação para pacientes com Doença Renal Crônica em estágio terminal. O aumento da sobrevida do enxerto tem sido um desafio constante, existindo a necessidade de um monitoramento contínuo para que precocemente seja detectada uma disfunção do enxerto e tomada de decisões, evitando a rejeição. Evidências sugerem que a inflamação persistente e o estresse oxidativo começam precocemente no processo de queda da função renal, apontando o valor potencial dos marcadores inflamatórios em pacientes transplantados renais como preditor de disfunção do enxerto. Com o objetivo de investigar o perfil da cistatina C (CysC), interleucina 2 (IL-2), interleucina 6 (IL-6) e fator de necrose tumoral alfa (TNF-α) em receptores de transplante renal, analisou-se no período do pré transplante, com 30 e 180 dias do pós transplante através do método imunonefelométrico, a CysC sérica e através dos ensaios imuno enzimáticos humanos, os níveis séricos de IL-2, IL-6 e TNF-α em 23 pacientes que realizaram transplante renal com faixa etária compreendida entre 18 e 60 anos, transplantados com rim de doador vivo e que assinaram o termo de consentimento livre e esclarecido. 19 pacientes foram submetidos ao esquema de imunossupressão compreendendo inibidor de calcineurina (INC) (Tacrolimus), Micofenolato de Mofetil e Prednisona e 04 pacientes ao esquema INC (Ciclosporina), Azatioprina e Prednisona. 08 pacientes receberam indução, sendo 6 com anticorpo monoclonal (Basiliximab) e 2 com anticorpo policlonal (Timoglobulina), e 15 não receberam indução. A média de idade dos pacientes foi de 34,3 anos (± 11,7), havendo predominância do sexo feminino (52%) e da etnia negra (61%). Na internação, as médias de peso, peso seco, altura, pressão diastólica e sistólica, hemoglobina, albumina, fósforo e creatinina encontradas foram de 55,2Kg (± 14,0), 54,7Kg (±13,3), 158 cm (± 0,1), 133 mmHg (±21,6), 88 mmHg (±15,6), 11,7 g/dL (±1,9), 4,1 mg/dL (±0,5), 6,2 mg/dL (±1,7) e 8,9 mg/dL(±4,1) respectivamente, havendo um predomínio de doenças não glomerulares como doença de base. Quando comparados entre si, nos diferentes tempos de coleta, a CysC e creatinina (Cr) apresentaram diferença significante entre a internação e com 30 dias do pós-transplante (p<0,0001) e entre a internação e com 180 dias do pós-Transplante (p<0,0001), a IL-2 com 30 e 180 dias do pós-transplante (p = 0,0418) e TNF-α na internação e com 30 dias do pós-transplante (p=0,0001). Observou-se uma correlação negativa estatisticamente significante da CysC com TNF-α na internação e IL-6 com 180 dias do pós-transplante. Quando comparados os pacientes biopsiados e não biopsiados, a Cr e a CysC apresentaram diferença estatísticamente significante nos pacientes biopsiados com 30 e 180 dias do pós-transplante. Esses resultados indicam que não existe correlação significativa entre os níveis séricos de CysC, IL-2, IL-6 e TNF-α em um seguimento a curto prazo de receptores de transplantados renais. Nos pacientes submetidos à biópsia e não biopsiados, os níveis de CysC foram muito similares aos níveis de creatinina, ao contrário da IL-2, IL-6 e TNF-α, sendo necessário a realização de novos estudos para avaliação do perfil destes marcadores a longo prazo. ______________________________________________________________________________ ABSTRACT
Kidney transplantation is the best therapeutic and rehabilitation option for patients with end-stage chronic kidney disease. The increase of graft survival rate has been a constant challenge. It is necessary a continuous monitoring in order to detect as soon as possible a graft dysfunction and so that the implementation of a decision for preventing graft rejection. Evidences suggest that persistent inflammation and oxidative stress begin early in the process of a failing kidney function, indicating the potential importance of inflammatory markers in kidney transplant patients as a predictor of graft dysfunction. We aimed to investigate the profile of cystatin C (CysC), interleukin 2 (IL-2), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in kidney transplant recipients. We performed the analyses before transplantation and within 30 and 180 days after transplantation. For the serum CysC we used the immunonephelometric assay, and for IL-2, IL-6 and TNF-α, the human enzyme immunoassay. We investigated 23 patients whose ages were between 18 and 60 years and who underwent living donor kidney transplantation. All patients signed a consent form. 19 patients underwent immunosuppressive regimen consisting of calcineurin inhibitor (CNI) (tacrolimus), mycophenolate mofetil and prednisone. Other 04 patients received CNI (cyclosporin), azathioprine and prednisone. 08 patients received induction therapy, with 6 of them, with monoclonal antibody (Basiliximab) and 2 with polyclonal antibody (Thymoglobulin). 15 did not receive induction. The patient’s average age was 34.3 years (± 11.7), with more females (52%) and black ethnicity (61%). The weight, dry weight, height, systolic and diastolic blood pressure, hemoglobin, albumin, creatinine and phosphorus averages, at admission to the hospital, were 55.2 kg (± 14.0), 54.7 kg (± 13.3), 158 cm (± 0.1), 133 mmHg (± 21.6), 88 mmHg (± 15.6), 11.7 g / dL (± 1.9), 4.1 mg / dL (± 0.5) , 6.2 mg / dL (± 1.7) and 8.9 mg / dL (± 4.1) respectively. The non-glomerular diseases were more prevalent as underlying disease. When compared each other at different times of collection, CysC and creatinine (Cr) showed a significant difference (p <0.0001) between admission and 30 days after transplantation and between admission and 180 days after transplantation (p <0.0001); IL-2, between 30 and 180 days after transplantation (p = 0.0418) and TNF-α between admission and 30 days after transplantation (p = 0.0001). A statistically significant negative correlation of CysC with TNF-α at admission, and IL-6 within 180 days after transplantation was observed. When comparing patients who underwent biopsy and those who did not, the Cr and CysC had a statistically significant difference in patients biopsied between 30 and 180 days post-transplantation. These results indicate that there is no significant correlation between serum CysC, IL-2, IL-6 and TNF-α in a short-term follow-up of renal transplant recipients. In patients who underwent biopsy and those who did not, the levels of CysC and creatinine were very similar, unlike IL-2, IL-6 and TNF-α. It is necessary to perform new studies to evaluate the profile of these markers on long term.
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Khurram, Muhammad Arslan. « Transplantation with kidneys removed for small renal tumours : immunosuppressive strategies and role of rejection ». Thesis, University of Sunderland, 2017. http://sure.sunderland.ac.uk/8559/.
Texte intégralRésumé :
Renal transplantation is the definitive treatment for the end-stage renal failure. Despite concerted efforts to increase the number of available organs there remains a wide gap. Kidneys with small renal cell carcinoma have been used for transplantation after ex vivo resection of tumours with excellent results. Concerns regarding the behaviour of tumour under standard immunosuppression prevent this source from being popularised. We studied tumour behaviour with standard immunosuppression and immunosuppressives with anti-proliferative properties and the effect of MHC matching on tumour behaviour. Luciferase labelled Wistar rat kidney tumour cells were injected subcutaneously into Wistar or Lewis rats to mimic well and poorly matched groups. These were divided into groups receiving Cyclosporine, Sirolimus high and Sirolimus low dose and Leflunomide. Effects of matching on tumour rejection were studied by immunosuppression withdrawal in half of the animals within each group. Tumour progression was monitored with IVIS spectrum imaging system. When the immunosuppression was continued for the length of the study period with Cyclosporine immunosuppression, the tumour continued to grow in both strains. With high dose Sirolimus, the tumour was eradicated within 2 weeks in both Wistar and Lewis rats (p < 0.05). Both strains receiving low dose Sirolimus also eradicated the tumour within four weeks of treatment (p < 0.05). In Leflunomide group, 4/7 animals rejected the tumour within the 4 weeks of study period (p < 0.05). To study the effects of rejection and matching on the tumour behaviour, the immunosuppression was stopped after 2 weeks of treatment and the animals followed for another two weeks to study these effects. After treatment withdrawal, the tumour rejection was noted which was significantly stronger in poorly matched animals than in well-matched animals (p < 0.05) in cyclosporine treated animals. These results appeared to be in line with our hypothesis, that newer immunosuppressive medications with anti-neoplastic effects may be better options after transplanting kidneys after small tumour ex-vivo resection. Acute rejection showed significant ability to lead to tumour eradication, more effectively in less well-matched animals than well-matched combinations. Thus perhaps clinically, recipients of such restored kidneys should be less well matched and immunosuppressed with agents with anti-proliferative properties. These results will need to be replicated with further studies including closely monitored clinical studies before it can be popularised at a significant new source of precious organs.
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Terachi, Toshiro. « Coexistence of Autologous Antibodies and Decay-accelerating Factor, an Inhibitor of Complement, on Human Renal Tumor Cells ». Kyoto University, 1993. http://hdl.handle.net/2433/168843.
Texte intégralRésumé :
本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものであるKyoto University (京都大学)
0048
新制・論文博士
博士(医学)
乙第8045号
論医博第1414号
新制||医||552(附属図書館)
UT51-93-B317
(主査)教授 湊 長博, 教授 日合 弘, 教授 吉田 修
学位規則第4条第2項該当
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Petit, Montserrat Ana. « Expressió de KIT i PDGFR en tumors de cèl·lules renals. Discussió del seu paper com a possibles dianes terapèutiques ». Doctoral thesis, Universitat de Barcelona, 2008. http://hdl.handle.net/10803/694.
Texte intégralRésumé :
En els darrers anys s´ha consolidat l´enfoc translacional en l´abordatge del càncer. Aquest es basa en la voluntat de comprendre la biologia tumoral i implementar clínicament aquest coneixement dissenyant nous fàrmacs capaços d´inhibir específicament molècules oncogèniques.En aquest context, s´han descobert els receptors tirosina-quinasa (RTK) com a proto-oncogens crucials en la diferenciació i proliferació cel·lular i com a molècules amb un gran paper en carcinogènesi.
KIT i PDGFR són dos exemples paradigmàtics de RTK pels que s´han desenvolupat fàrmacs inhibidors, amb gran èxit terapèutic en aquells tumors, com el GIST, on aquestes proteïnes tenen un paper patogenètic crucial.
L´enfoc translacional ha tingut un gran impacte en el camp dels tumors renals que representen un 3% dels tumors de l´economia i dels quals s´en reconeixen diferents subtipus. Els avenços en biologia molecular han permès definir la patogènia d´algunes entitats, sobretot del Carcinoma renal de cèl·lula clara (CRCC), un dels subtipus tumorals freqüents i més agressiu per l´alt nombre de pacients que desenvolupen malaltia metastàtica (30-50%) i pels quals s´estan buscant noves eines terapèutiques.
Pel valor oncogènic i com a dianes terapèutiques del KIT i PGFR, aquest treball té com a objectiu estudiar l´expressió d´aquestes proteïnes per immunohistoquímica sobre teixit de tumors de cèl·lules renals. A més a més, en base a aquests resultats i la literatura es pretén discutir el seu valor com a dianes terapèutiques.
En el nostre estudi es va demostrar expressió de KIT de forma específica en Carcinoma renal Cromòfob (ChRCC) i Oncocitoma (OR).
També es va trobar sobreexpressió de KIT i PDGFRα en la diferenciació sarcomatoide de carcinomes renals (SRCC) sense que aquesta s´associès amb mutacions en els exons 9, 11, 13, 17 del KIT ni en els exons 11, 12, 17, 18 de PDGFRα; que són els més freqüent mutats en el GIST .
Alhora vam observar expressió inespecífica en cèl·lules tumorals de PDGFRα i PDGFRβ en un baix nombre de casos i de forma dèbil en diferents subtipus de tumors renals. Per contra, vam evidenciar sobreexpressió de PDGFRβ vascular de forma característica en un alt percentatge de CRCC.
En base als nostres resultats, proposem la utilitat de KIT com a marcador en el diagnòstic diferencial de diferents subtipus tumorals.
Alhora, hem demostrat que l´expressió de KIT i PDGFRα en els SRCC no segueix el mateix model patogenètic que el GIST.
La literatura sosté la necessitat de demostrar la implicació patogènica d´una proteïna en un tumor per plantejar l´efectivitat de la seva inhibició selectiva, essent l´expressió immunohistoquímica per si mateixa insuficient per sostindre aquest principi.
Fins al moment, no es coneix si KIT i PDGFR tenen un paper oncogènic en el ChRCC, OR i en SRCC.
Per tant, no hi ha suficients dades per proposar l´us d´inhibidors proteics contra aquestes proteïnes en ChRCC i SRCC disseminats.
Per altra banda l´expressió vascular de PDGFRβ en CRCC si que té una base patogenètica ja que el seu lligand (PDGF) s´ha implicat directament en la seva biologia.
Alhora aquesta expressió vascular és coherent amb els estudis que relacionen la isoforma beta del PDGFR amb la maduració dels pericits i en la promoció de l´angiogènesi.
Per tant, els nostres resultats sostenen la relació del PDGFRβ en la patogènia del Carcinoma renal de cèl·lula clara i el valor terapèutic dels fàrmacs contra aquest receptor amb finalitat antiangiogènica.
En conclusió, en el context de l´enfoc translacional del càncer i la necessitat d´implementació de nous fàrmacs inhibidors proteics pel tractament del carcinoma renal metastàtic, l´anàlisi d´expressió de RTK en tumors renals permet juntament amb la integració d´altres estudis, la discussió del valor diagnòstic i sobretot terapèutic d´aquestes dianes moleculars.
Renal Cell Neoplasms (RCN) represent 3% of cancer incidence and comprise different clinicopathologic entities. Malignant subtypes, specially the most frequent one Clear Cell Renal Cell Carcinoma (CRCC), remain the most lethal of urologic cancers due to the high rate of patients (30-50%) developing metastatic disease for whom new therapies are needed.
Great advances in molecular biology have led to the identification of tyrosine-kinase receptors (TKR) as relevant proteins in tumorigenesis. Moreover the advent of selective inhibitors against them has raised interest on its expression in different tumors.
PDGFR and KIT are two examples of TKR that have an oncogenic role in numerous neoplasms and can be inhibited pharmacologically.
Because of its potential role as proto-oncogens and therapeutic targets; We aimed to study its immunohistochemical expression in RCN and to discuss its possible role as molecular targets.
Our results highlight specific expression of KIT in Chromophobe renal cell carcinoma (ChRCC) and Renal Oncocytoma (RO). Overexpression of KIT and PDGFRα was found in sarcomatoid differentiation of renal tumours (SRCC) without mutations in KIT exons 9,11,13,17 nor PDGFR exons 11,12,17,18 which are the most commonly mutated in GIST.
Moreover inespecific and low expression of PDGFRα and PDGFRβ was evidenced in tumoral cells in different RCN. In contrast, vascular expression of PDGFRβ was seen caracteristically in half of CRCC cases.
According to our results, we propose KIT as a useful marker for differential diagnosis among RCN.
Moreover we demonstrate that expression of KIT and PDGFR in SRCC doesn´t follow the same pathogenetic mecanism as GIST.
Scientific community claims that immunohistochemical expression of a protein in a tumor is not enough to propose it as a therapeutic target and that demonstation of its pathogenetic role is needed.
So as, there is still no evidence of participation of KIT-PDGFR in ChRCC, OR nor SRCC oncogenesis, there is not enough data to propose them as therapeutic targets.
Conversely, in different studies PDGFRβ has been involved in CRCC pathogenesis and has been related to tumor angiogenesis by perycite recruitment. So that, vascular expression of PDGFRβ in CRCC favours its consideration as a therapeutic target in this tumor subtype.
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Zampolli, Hamilton de Campos. « Avaliação dos efeitos antineoplásicos do Amblyomin-X em carcinoma de células renais ». Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-10022012-151003/.
Texte intégralRésumé :
Introdução: O carcinoma de células renais metastático (CCRm) é um tumor altamente agressivo e resistente. Seu tratamento é baseado em terapia alvo molecular e citocinas. Avaliamos os efeitos antineoplásicos do Amblyomin-X, sobre CCR. Métodos: Avaliadas culturas de CCR RENCA e fibroblastos normais NIH/3T3 tratadas ou não com Amblyomin-X. Realizados ensaios de viabilidade celular por MTT e determinação, por citometria de fluxo, da proporção de células em apoptose/necrose; expressão da P-gp; Bad; Bax; Bcl-2; ciclina D1; caspase 3; Ki-67; p53; VEGFR1; citocromo c; análise das fase do ciclo celular; e atividade do proteassoma. Analisamos as populações celulares por microscopia eletrônica de varredura. Empregados testes T e One-way ANOVA para análise estatística. Resultados: O Amblyomin-X demonstrou citotoxicidade em células RENCA por indução de apoptose, diminuição de proliferação celular, inibição do proteassoma e modulação do ciclo celular em G0/G1. Em fibroblastos normais não houve citotoxicidade Conclusão: O Amblyomin-X apresentou efeito antineoplásico em CCR e não exerceu efeito citotóxico em células normais, demonstrando um possível potencial terapêutico no tratamento do CCRm. Estudos futuros deverão confirmar estes resultados.Introduction: Metastatic renal cell carcinoma (mRCC) is a highly agressive and resistant tumour. Its treatment is based on targeted therapies and cytokines. We have evaluated the antineoplasic effects of Amblyomin-X on RCC. Methods: RCC (RENCA) and fibroblasts (NIH/3T3) cell cultures treated or not with Amblyomin-X were evaluated. MTT assay was performed to determine cell viability. Apoptosis/necrosis ratio; expression of P-gp; Bad; Bax; Bcl-2; cyclin D1; caspase-3; Ki-67; p53; VEGFR1; cytochrome c; cell cycle analysis and proteasome activity were obtained by flow cytometry. Cellular populations were analised by Scanning Electron Microscopy. Statistical analyses was performed using T-Tests and One-way ANOVA. Results: Amblyomin-X showed cytotoxic activity on RENCA tumor cells. It has induced apoptosis, decreased tumor cell proliferation, targeted the ubiquitinproteasome system and modulated genes related to cell cycle in G0/G1. There was no toxicity on fibroblasts. Conclusion: Amblyomin-X showed antineoplasic effects on RCC cells preserved normal fibroblast cells. There is a potential role of its therapeutic use in mRCC treatment. Future studies should confirm our initial results.
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Kiweler, Nicole [Verfasser]. « Impact of class I HDACs and their inhibitors on renal and colorectal tumor cell fate decisions / Nicole Kiweler ». Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1193687411/34.
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Senatore, Marcela Andrea Duran Haun 1974. « Meta-análise : estudos da efetividade de terapias com fármacos alvo moleculares para o tratamento do tumor renal metastático ». [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313127.
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Orientadores: Wagner Eduardo Matheus, Ubirajara FerreiraTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Atualmente existem diferentes agentes para o tratamento do câncer renal avançado. O objetivo principal desse trabalho foi realizar revisão sistemática com meta-análise dos estudos clínicos randomizados que compararam: sorafenibe, sunitinibe, bevacizumabe, temsirolimus e everolimus ao interferon-?. Para isto foi realizada revisão sistemática da literatura em diferentes bancos de dados: EMBASE, LILACS e PUBMED, identificando estudos clínicos randomizados que compararam as terapias alvo moleculares (TAM) disponíveis versus interferon-alfa para tratamento de pacientes com câncer renal avançado. Para o tratamento de 1a linha foram encontrados 10 estudos que avaliaram as terapias com sunitinibe, sorafenibe, bevacizumabe e temsirolimus; e três estudos que avaliaram o sorafenibe e everolimus como tratamento de 2a linha. O Risco Relativo (RR) da sobrevida livre de progressão (SLP) dos estudos de 1a linha foi de 0.83, intervalo de confiança (IC) [0.78-0.87] com I2= 94% e p<0.00001. Os melhores resultados foram: o estudo do sunitinibe, 0.38, IC [0.25-0.58], do bevacizumabe com RR de 0.62, IC [0.47-0.83] e do temsirolimus, 0.78, IC [0.70-0.87]. A meta-análise não demonstrou benefício quanto à sobrevida global (SG), no tratamento de 1a linha com sunitinibe e temsirolimus. Os tratamentos de 1ª linha com sorafenibe e bevacizumabe não associaram benefícios clínicos significativos. Não foi possível realizar meta-análise nos estudos do tratamento de 2a linha, pois, as populações eram diferentes. Logo, para o tratamento de 1a linha, sunitinibe e temsirolimus foram a terapias mais efetivas, quanto a SLP. No tratamento de 2a linha, o sorafenibe e everolimus foram relacionados à melhora da SLP. Em todos os estudos de 1a linha os pacientes não apresentaram melhora de SG e a qualidade metodológica não foram adequadas, portanto esses resultados devem ser analisados com cautela
Abstract: Currently, there are different agents for the treatment of advanced kidney cancer. The main aim of this study was to perform a systematic review and meta-analysis of randomized clinical trials that compared: sorafenib, sunitinib, bevacizumab, temsirolimus and everolimus. It was performed a systematic review of the literature in different databases: EMBASE, LILACS and PubMed, identifying randomized clinical trials that compared the available therapies target cells versus alpha-interferon for the patient treatments with advanced kidney cancer. For the treatment of first-line were found 10 studies that evaluated the therapy with sunitinib, sorafenib, bevacizumab and temsirolimus and three studies evaluating sorafenib and everolimus as a treatment second-line. The relative risk of progression free survival of first line studies was 0.83, confidence interval (CI) [0.78-0.87] with I2 = 94% and p <0.00001. The best results were: the study of sunitinib, 0.38, CI [0:25 to 0:58], bevacizumab with RR of 0.62, CI [0.47-0.83] and temsirolimus, 0.78, CI [0.70-0.87]. The meta-analysis showed no benefit on overall survival in first-line treatment with sunitinib and temsirolimus. The first-line treatment with sorafenib and bevacizumab not associated significant clinical benefits. Unable to perform meta-analysis on studies of second-line treatment, because the cohorts were different between them. For the treatment of first-line, sunitinib and temsirolimus were more effective therapies, as the progression free survival (PFS). In the second line treatment, sorafenib and everolimus was associated with improved PFS. In these studies, patients showed no improvement in overall survival (OS) and methodological quality were not adequate, so these results should be analyzed with caution
Doutorado
Fisiopatologia Cirúrgica
Doutora em Ciências
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Harten, Sarah Kay. « Role of the von Hippel-Lindau tumour suppressor gene in regulating renal epithelial cell characteristics ». Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490934.
Texte intégralRésumé :
Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene underlies both VHL disease, an inherited multi-cancer syndrome, and the majority of sporadic clear cell renal cell carcinomas (CCRCCs). The best established function of pVHL is regulation of HIF (hypoxia inducible factor). However, how VHL functions as a renal tumour suppressor gene remains to be fully elucidated. There is extensive evidence that changes in cell-cell adhesion and loss of epithelial cytoarchitecture are pivotal in the progression of tumours of epithelial origin, allowing cell-cell dissociation and subsequent invasion. The main objective of this thesis has been to identify whether VHL regulates epithelial cell characteristics, and, if so, whether this is mediated via HIF. The major findings are as follows: First, VHL loss-of-function has striking effects on the expression and localisation of several tight junction (TJ) components (occludin, claudin 1 and ZO-l) in both VHL defective CCRCC cells and sporadic CCRCC tissue (compared to adjacent unaffected kidney). Secondly disruption of TJs was detected in the earliest lesions of VHL inactivation in VHL patient kidneys, suggesting a potential role in tumour initiation. Thirdly re-expression the adherens junction (AJ) protein E-cadherin did not rescue TJ formation, showing that the TJ defect occurs independently of AJ breakage. Fourthly, VHL is required for formation of the primary cilium, a luminal hair-like structure which senses renal tubular flow and which is disturbed in most renal cystic diseases. Finally activation of HIF promotes dedifferentiation of renal epithelial cells. Dedifferentiation may allow cells to tolerate further mutations and undergo full malignant transformation. I have also shown that HDAC inhibitors can reverse this phenotype and therefore may be of use therapeutically. In summary, the work presented in this thesis provides significant insights into understanding how the VHL/HIF pathway contributes to tumour development in both VHL defective renal cancers and hypoxic non-renal tumours.
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Li, Xingru, Sihan Wang, Raviprakash Tumkur Sitaram, Charlotta Andersson, Börje Ljungberg et Ai-Hong Li. « Single Nucleotide Polymorphisms in the Wilms' Tumour Gene 1 in Clear Cell Renal Cell Carcinoma ». Umeå universitet, Klinisk kemi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-70351.
Texte intégralRésumé :
The Wilms' tumour gene 1 (WT1) single nucleotide polymorphism (SNP) rs16754 has recently been described as an independent prognostic factor in acute myeloid leukaemia (AML) patients. It is of great interest to test whether WT1 SNPs can be used as a molecular marker in other cancer types in order to improve risk and treatment stratification. We performed sequencing analysis on all 10 exons of the WT1 gene in a total of 182 patients with clear cell renal cell carcinoma (ccRCC). Six different SNPs were identified, in descending order for minor allele frequency: rs2234582, rs16754, rs1799925, rs5030315, rs2234583, and rs2234581. At least one minor allele for WT1 SNP was identified in 61% of ccRCC patients. In the entire study population, only 6% carried two copies of the minor allele. The genotypes of WT1 SNPs in 78 tumour-free kidney tissue specimens were found to be in 95% concordance with corresponding tumour samples. No correlation was observed between WT1 SNP genotypes and RNA expression level. WT1 SNP genotypes did not associate with clinical and pathological characteristics. We found favourable outcomes associated with the homozygous minor allele for WT1 SNP. However, SNP genotypes did not show to be of prognostic significance when comparing wild-type versus homozygous or heterozygous for the minor allele in the entire cohort. None of the previously reported WT1 mutations in AML was found in the present study. A novel WT1 missense mutation was identified in only one patient. Our data suggest that common WT1 mutations are not involved in ccRCC. Due to too few cases harbouring the homozygous minor allele, the prognostic impact needs to be verified in larger study populations.