No description available.

Se investigan la prevalencia y características generales de los tumores de la glándula adrenal en 10.000 vacas de 5 a 13 años, faenadas en un frigorífico de la Provincia de Buenos Aires. Se describen las características macroscópicas e histopatológicas de 136 lesiones halladas en 124 animales, que incluyen 33 feocromocitomas, 26 adenomas y 18 carcinomas corticales, 22 neurofibromas y un neuroblastoma. Igualmente se consideran las lesiones seudotumorales que incluyen hiperplasia cortical focal, "mielolipoma", focos de tejido hemopoyético y nódulos de células claras. Se analizan los datos obtenidos sobre influencia geográfica y la edad, tipo y estado general de los animales afectados. / The prevalence and general characteristics of adrenal tumors among 10.000 cows from 5 to 13 years old, slaughtered at an establishent in Buenos Aires province, were investigated. Macroscopic and histopathologic charasteristics of 136 lesions found in 124 animals were described; they included 33 pheochromocytomas, 26 adenomas and 18 cortical carcinomas, 22 neurofibromas and 1 neuroblastoma. Tumor-like lesions were also considered; they included focal cortical hyperplasia, "myelolipoma", haemotopoietic foci and clear cell nodule. Collected data on geographic influence, age, breed and carcass condition of the affected animals were evaluated.

While extirpative surgery is curative for localized clear cell renal cell carcinoma (ccRCC), many patients develop recurrences or present with metastatic disease. Several aspects of ccRCC biology have been investigated, but these have been done in cell lines, which are known to poorly represent the tumour. Since cell lines are amenable to a wide array of experimental testing, the studies presented here demonstrate a novel method to generate ccRCC cell lines from primary tumours, which increases the rate of primary tumour cell line generation four fold. Additionally, ccRCC cells do not grow in serum-free media, which has been shown to be beneficial in other cancers. Therefore, we interrogated the effect of exogenous growth factors to optimize our serum-free media growth conditions, among which TGFb1 appeared to elicit the largest mitogenic effect. Once optimized, these findings will provide a valuable tool for understanding ccRCC tumour cell biology and identifying therapeutic targets.

While extirpative surgery is curative for localized clear cell renal cell carcinoma (ccRCC), many patients develop recurrences or present with metastatic disease. Several aspects of ccRCC biology have been investigated, but these have been done in cell lines, which are known to poorly represent the tumour. Since cell lines are amenable to a wide array of experimental testing, the studies presented here demonstrate a novel method to generate ccRCC cell lines from primary tumours, which increases the rate of primary tumour cell line generation four fold. Additionally, ccRCC cells do not grow in serum-free media, which has been shown to be beneficial in other cancers. Therefore, we interrogated the effect of exogenous growth factors to optimize our serum-free media growth conditions, among which TGFb1 appeared to elicit the largest mitogenic effect. Once optimized, these findings will provide a valuable tool for understanding ccRCC tumour cell biology and identifying therapeutic targets.

In der vorliegenden Arbeit werden mit den Jahren 2005/2006 und 2007 qualitätsrelevante Parameter von Patienten mit einem kolorektalen Karzinom vor und unmittelbar nach Gründung des Darmzentrums an der Universitätsklinik Leipzig analysiert. Ziel dieser Arbeit war es zu untersuchen, welchen Einfluss die Gründung eines zertifizierten Darmzentrums kurzfristig auf die Behandlungsqualität von Patienten mit einem kolorektalen Karzinom hat. Die durch die Deutsche Krebsgesellschaft festgelegten Struktur- bzw. Ergebnisparameter wurden für die Jahre 2005 und 2006 retrospektiv - ab 2007 kontinuierlich erfasst. Die meisten, aber nicht alle Anforderungen der Deutschen Krebsgesellschaft wurden erreicht, bzw. umgesetzt. So zeigte sich eine bessere Dokumentation der Behandlung, insbesondere in der Pathologie. Ausserdem konnte eine Zunahme der Fallzahlen verzeichnet werden. Die Ergebnisse der Arbeit zeigen, dass durch eine Zertifizierung als Darmzentrum zunächst eine Verbesserung der Dokumentation und Standardisierung der Therapie bewirkt werden kann. Kurzfristig kann in einigen, aber nicht allen Behandlungsparametern, eine Qualitätsverbesserung, insbesondere in der Chirurgie, erreicht werden.

No description available.

T cells are a crucial component of the immune system and play an important role in responses to pathogens, tumours, and transplanted tissues. In many human cancers, elevated numbers of tumour-infiltrating CD8+ killer T cells are associated with favourable outcomes, suggesting that enhancing T-cell responses could provide major therapeutic benefit for cancer patients. Thus, identifying factors that can promote protective T-cell responses is of great clinical importance. The cytokine interleukin-2 (IL-2) is a major inducer of T-cell proliferation and differentiation, and is used clinically to treat melanoma and renal cell carcinoma. The first two chapters of this thesis focus on the biochemical mechanisms by which IL-2 induces T-cell proliferation. By using mutant and chimeric cytokine receptors expressed in lymphocyte cell lines, the interplay between Shc and STAT5, two major mitogenic signaling pathways activated by the IL-2 receptor, are investigated, revealing an essential synergy between the two pathways for optimal lymphocyte proliferation. The third chapter of this thesis describes work done to identify cytokines that promote T-cell responses within the ovarian cancer microenvironment. In human diseases such as HIV/AIDS and cancer, high numbers of “polyfunctional” T cells (i.e., T cells capable of multiple effector functions) are associated with favourable outcomes. Using clinical ovarian cancer samples in a novel ex vivo assay, it was found that the ovarian tumour environment inhibits polyfunctional T-cell responses to varying extents among patients. After surveying a large panel of cytokines, the cytokine combination of IL-2, IL-12, and IL-18 was found to overcome the immunosuppressive environment to potently enhance CD8+ T-cell proliferation and polyfunctionality in all patient samples. The polyfunctional profiles induced by these cytokines are associated with protective immunity in various human conditions. Thus, these findings suggest that given the right signals, T cells can become highly polyfunctional effectors in the ovarian cancer microenvironment, which offers promise for the development of effective T-cell based therapies for this clinically challenging disease. / Graduate / 0982

Proper control of Hedgehog (Hh) signaling is critical for hair follicle morphogenesis and ectopic Hh pathway activity is a hallmark of basal cell carcinoma (BCC), the most common type of skin cancer. Mutations in Hh pathway components such as the Hh-binding receptor PATCHED1 (PTCH1) are frequently found in BCC. However, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formation remains poorly understood. Gli2, the major mediator of Hh signaling is essential for hair follicle development and its overexpression in the epidermis induces BCC formation. Despite the importance of Gli2 in the skin, how it is regulated during skin development and tumorigenesis is unclear. Using a genetic approach with loss-of-function mouse mutants and primary keratinocyte cultures, I have uncovered the distinct and overlapping functions of Sufu and Kif7, two evolutionarily conserved regulators of the Hh pathway, during skin development and tumorigenesis. Sufu and Kif7 play opposing roles in Hh signaling through the regulation of Gli2 subcellular distribution, and Kif7 performs distinct Sufu-dependent and –independent functions. In addition, deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate and compromised epidermal differentiation. In the adult skin, inactivation of Sufu does not drive BCC formation and requires additional genetic alterations such as the loss of Kif7. Using a Ptc1 mouse model for BCC, I have identified previously unrecognized molecular pathways and cellular events involved in BCC pathogenesis. This includes, aberrant cell cycle progression, loss of cell cycle checkpoint regulation, and suppression of the p53 response. Overall my work provides critical insight into the molecular control of Hh signaling and the downstream events driving BCC formation.

Proper control of Hedgehog (Hh) signaling is critical for hair follicle morphogenesis and ectopic Hh pathway activity is a hallmark of basal cell carcinoma (BCC), the most common type of skin cancer. Mutations in Hh pathway components such as the Hh-binding receptor PATCHED1 (PTCH1) are frequently found in BCC. However, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formation remains poorly understood. Gli2, the major mediator of Hh signaling is essential for hair follicle development and its overexpression in the epidermis induces BCC formation. Despite the importance of Gli2 in the skin, how it is regulated during skin development and tumorigenesis is unclear. Using a genetic approach with loss-of-function mouse mutants and primary keratinocyte cultures, I have uncovered the distinct and overlapping functions of Sufu and Kif7, two evolutionarily conserved regulators of the Hh pathway, during skin development and tumorigenesis. Sufu and Kif7 play opposing roles in Hh signaling through the regulation of Gli2 subcellular distribution, and Kif7 performs distinct Sufu-dependent and –independent functions. In addition, deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate and compromised epidermal differentiation. In the adult skin, inactivation of Sufu does not drive BCC formation and requires additional genetic alterations such as the loss of Kif7. Using a Ptc1 mouse model for BCC, I have identified previously unrecognized molecular pathways and cellular events involved in BCC pathogenesis. This includes, aberrant cell cycle progression, loss of cell cycle checkpoint regulation, and suppression of the p53 response. Overall my work provides critical insight into the molecular control of Hh signaling and the downstream events driving BCC formation.

El objetivo de la presente tesis doctoral era estudiar los mecanismos de invasión, el papel de diferentes factores de crecimiento, el estudio de la vía PI3K/Akt/mTOR y evaluar la respuesta al tratamiento en el cáncer de mama. Previamente habíamos estudiado las mutaciones del PIK3CA en una serie de pacientes con carcinoma de mama en las que encontramos asociación de mutaciones de PIK3CA con el subgrupo de los pacientes con tumores HER2 +. Además la presencia de mutaciones de PIK3CA se asoció a peor supervivencia. La introducción de trastuzumab ha cambiado la historia natural de las pacientes con tumores HER2+ por lo tanto decidimos incorporar al estudio pacientes que habían recibido este fármaco. En este artículo encontramos al menos una alteración de la vía PI3K en un cuarto de los tumores, además demostramos las complejas interacciones entre EGFR, IGFR1R i la vía PTEN/PI3K/Akt/Bad y mTOR, que están relacionados con mecanismos de resistencia a trastuzumab. Para completar el estudio decidimos analizar otro receptor de membrana, como LRP-1 o “low density lipoprotein receptor-related protein 1”. Este es un miembro de la familia de receptores de colesterol que presenta homología parcial con EGFR. En nuestro estudio detectamos la expresión de LRP1 en el 14% de los tumores, además esta se correlacionaba con alto grado nuclear, alto índice mitótico y Ki67 elevado. Además la expresión de LRP1 se asoció a tumores de tipo triple negativo que sobreexpresaban EGFR y HER2+. El síndrome hipermetabólico (obesidad, intolerancia a la glucosa, bajo HDL, hipertrigliceridemia e hipertensión) se ha asociado a tumores de tipo triple negativo. En nuestra serie las pacientes con tumores de tipo triple negativo y HER2+ mostraron mayores niveles de colesterol. Se ha relacionado la sobreexpresión de LRP1 con hipercolesterolemia en estudios “in vivo”. En nuestra serie encontramos mayores cifras de colesterol en las pacientes que sobreexpresaban LRP1, aunque los resultados no fueron estadísticamente significativos. En conclusión hemos corroborado la importancia que tienen los receptores de membrana en el cáncer de mama. También que el estado de activación de los diferentes efectores de la vía del PI3K/akt/mTOR pueden influir en la resistencia a fármacos como Trastuzumab. También hemos demostrado que otros receptores de membrana como LRP1 (con homología parcial con EGFR) están implicados en el carcinoma de mama y se relacionan con la invasión. Además es muy interesante la relación de este último con los niveles de colesterol y el síndrome hipermetabólico. / The objective of the present thesis was to study the mechanisms of invasion, the role of different growth factor receptors, the impact of the PI3K/Akt/Mtor pathway and the response to treatment in breast carcinoma. In a previous study we found association of PIK3CA mutations with HER2 postive breast carcinomas, moreover PIK3CA mutations were associated with poor prognosis. The introduction of trastuzumab in the treatment of HER2 positive breast carcinoma has dramatically changed his natural history, for this reason we decided to select patients which has received trastuzumab in her treatment. We found in about one-forth of HER2 tumours at least one molecular alteration in the PI3K pathway and/or its upstream or downstream effectors. Our data support the complex interactions between EGFR, IGF1R, and the PTEN/PI3K/Akt/Bad and mTOR signalling pathway, which in turn are potentially related with the mechanisms of trastuzumab response. To complete our study we selected another membrane receptor such as low density lipoprotein receptor-related protein 1 or LRP-1. This receptor is a member of the cholesterol receptors and has partial homology with EGFR. In our study we found LRP-1 expression in 14% of the tumours and was related with high nuclear grade, high mitotic index and high proliferation index (Ki 67). Also, LRP-1 expression was present in HER2 positive and triple negative tumours with EGFR expression. The hypermetabolic syndrome (obesity, glucose intolerance, low HDL, hypertriglyceridemia and hypertension) has been associated with triple negative tumors. In our series patients with triple negative and HER2 positive tumors had higher cholesterol levels, although this association was not statistically significant. In conclusion we have confirmed the role of membrane receptors in breast carcinomas. Also activation of their downstream effectors such as the PI3K/akt/mTOR pathway can be related to trastuzumab resistance. We have demonstrated that other membrane receptors such as LRP-1 (with partial homology with EGFR) are related to breast carcinoma and their mechanisms of invasion. Moreover, the relationship between LRP-1 cholesterol levels and the hypermetabolic syndrome are very interesting, but further studies are needed.