As células intersticiais de Cajal (CIC) têm sido estudadas como participante do peristaltismo em vários sistemas. Sua presença no trato geniturinário pode sustentar a importância dessas células na fisiopatologia da estenose da junção ureteropielica (JUP). O Objetivo desse estudo foi avaliar a densidade das CIC em pacientes adultos e no final da adolescência, portadores de estenose da JUP, submetidos à pieloplastia e verificar se há associação entre a densidade das CIC com os achados clínicos e de imagem pré e pós-operatórios, notadamente ultrassonografia e cintilografia renal. Foram estudados 23 pacientes com estenose da JUP, submetidos à pieloplastia desmembrada pela técnica videolaparoscópica na Divisão de Clínica Urológica do Departamento de Cirurgia do HCFMUSP, de forma consecutiva, pelo mesmo grupo de cirurgiões, no período entre fevereiro de 2011 a janeiro de 2012. Foi realizada análise imunohistoquímica para expressão do receptor de tirosina quinase (c-KIT) em todas as amostras das JUP e quantificada a densidade das CIC. Os pacientes foram acompanhados periodicamente para avaliação da resposta clínica e dos exames de imagem. Foi encontrado que a média de idade da amostra foi de 34,83 anos. Houve predomínio do gênero masculino (56,5%). O rim direito foi o mais acometido (56,5%). A hidronefrose grave foi identificada na maioria dos pacientes (52,2%). A média da função renal do rim acometido estimada pela cintilografia, pré e pós-operatória foi de respectivamente, 33,7 e 33,4%. Dos 23 pacientes, 20 apresentaram melhora do padrão cintilográfico de drenagem ureteral. Houve predomínio de pacientes que apresentavam alta densidade das CIC (52,2%). Houve significância estatística quando associado a densidade das CIC e a melhora do padrão ultrassonográfico (p= 0,032). Contudo, não houve associação entre a densidade das CIC e as outras variáveis clínicas ou de imagem. Pode-se concluir que a densidade das CIC pode ser um bom preditor da resposta ultrassonográfica pósoperatória em pacientes adultos com estenose da JUP submetidos à pieloplastia / The interstitial cells of Cajal (ICC) have been studied as peristalsis participating in various systems. Its presence in the genitourinary tract can sustain the importance of these cells in the pathophysiology of ureteropelvic junction obstruction (UPJO). The aim of this study was to evaluate the density of ICC in adults and in the late adolescence patients with UPJO, undergoing pyeloplasty and to check if there is association of changes in the ICC density with clinical findings, as well as pre and postoperative images, especially ultrasound and diuretic radioisotope renography. We selected 23 patients with UPJO, undergoing laparocopic dismembered pyeloplasty in the Urology Division of the HC-FMUSP Department of Surgery, consecutively, by the same group of surgeons in the period between February 2011 and January 2012. It was performed immunohistochemical analysis for tyrosine kinase receptor expression (c-KIT) in all samples of UPJO quantified the ICC density. The patients were followed up periodically to evaluate the clinical response and imaging. The average age of the sample was 34.83 years. There was a predominance of males (56.5%). The right kidney was the most affected (56.5%). Severe hydronephrosis was identified in most patients (52.2%). The average renal function affected estimated by diuretic radioisotope renography, pre and post-operative was respectively 33.7 and 33.4%. Of the 23 patients, 20 had an improvement on diuretic radioisotope renography pattern of ureteral drainage. There was a predominance of patients with high ICC density (52.2%). There was statistical significance when associated with ICC density and the improvement of ultrasonographic pattern (p = 0.032). However, there was no association between the ICC density and other clinical or imaging variables. It can be concluded that the density of the ICC maybe a good predictor of post-operative ultrasound response in adult patients with UPJO undergoing pyeloplasty

子宮頸癌是全球女性中第三常見的癌症。人類乳頭瘤狀病毒（HPV）已被證實為引致子宮頸癌的主要因素。目前已發現了150多種HPV。HPV-52在世界上較為少見，但在亞洲，特別是東亞地區，卻相當流行。 / 本回顧性研究收集了303個HPV-52陽性的子宮頸樣本，其中185個來自香港，118個來自韓國首爾。我們通過對HPV基因組中E6、E7、L1和LCR區域進行擴增和測序，以檢測HPV-52變異株的序列多樣性和致癌風險。 / L1-LCR-E6-E7串聯片段佔據了HPV-52基因組全長的41%。由191條該種序列構建的系統發育樹顯示，HPV-52變異株進化成四個世系。原型系A進化系在香港和首爾都很少見，只占全部樣本的3.7%。B進化系（89.5%）則是最普遍的HPV-52病毒系。E6的最大序列差異為1.6%，L1（2.3%），E7（3.4%）和LCR（4.8%）依次增大。因此，E6作為最保守的基因組區域可作為HPV-52通用引物PCR的靶點，而E7更適宜作為特定變異株的PCR靶點。此外，在短片段序列中發現了可識別HPV-52進化系和進化枝的單核苷酸突變。它們可用於擴增斷裂的DNA片段或大規模實驗中。再者，進化壓力分析顯示E6、E7和L1三個編碼區域都經歷了強烈的淨化選擇作用。 / HPV-52進化系和常見變異株在香港和首爾的分佈情況沒有顯著差異。但E6中的nt 356G>A、nt 378A>C和nt 467C>A (N122K) 核苷酸突變只出現在香港樣本，而L1的nt 6239G>A以及LCR的nt 7395G>A和nt 7911A>C核苷酸突變只在首爾樣本中發現。HPV-52 E6的N122K突變對子宮頸癌有較高的致癌風險（P-value = 0.002）。E6中的nt 378A>C (P-value = 0.014) 同義突變, 以及LCR中的nt 7665G>A (P-value < 0.001)和nt 94G>A (P-value = 0.007)突變，亦與高致癌風險相關。LCR中的nt 7911A>C (P-value = 0.007)和nt 19T>C (P-value = 0.008) 突變則對子宮頸癌的發展有較低風險。HPV-52 E7或L1中的突變與子宮頸癌的發展無明顯關係。上述結果需要通過進一步研究證實。針對HPV-52序列變異的病毒學和作用機理的深入研究是必要的。 / Cervical cancer is the third most common cancer in women worldwide. It has been proven that human papillomavirus (HPV) is the primary causative agent of cervical cancer. To date, more than 150 HPV types have been characterized. HPV-52 is rare around the world but frequently detected in Asia, especially East Asia. / This retrospective study analyzed 303 cervical samples that 185 were collected from Hong Kong, and 118 were collected from Seoul, Korea. All samples were positive for HPV-52. HPV gene regions of E6, E7, L1 and LCR were amplified and sequenced to determine sequence diversity and risk association of HPV-52 variants between the two cities. / The 191 concatenated L1-LCR-E6-E7 sequences that comprised 41% of the whole HPV-52 genome displayed four distinct clusters. The prototype-like lineage A was rare in both cities, only found in 3.7% of all samples. Lineage B (89.5%) was found to be the most prevalent lineage. The maximum sequence divergence of E6 was 1.6%, followed by L1 (2.3%), E7 (3.4%) and LCR (4.8%). E6 being the most conserved region could be a target for HPV-52 consensus PCR, and E7 could be a target for variant-specific PCR. Besides, several single-nucleotide substitutions diagnostic for HPV-52 lineage and clade classification were identified within a few short fragments. They might be useful when handling fragmented DNA and being a more feasible approach in large-scale studies. Moreover, analysis of evolutionary pressure indicated that all the three encoding regions, E6, E7 and L1, underwent strong purifying selection. / No significant difference in the distribution pattern of HPV-52 lineages and common variants between Hong Kong and Seoul was observed. But nucleotide substitutions nt 356G>A, nt 378A>C and nt 467C>A (N122K) were only found in Hong Kong samples; whereas nt 6239G>A, nt 7395G>A and nt 7911A>C were exclusively found in samples from Seoul. A significantly higher risk for cervical cancer was found for the HPV-52 E6 variant N122K (P-value = 0.002). A synonymous substitution of E6, nt 378A>C (P-value = 0.014), as well as two nucleotide substitutions of LCR, nt 7665G>A (P-value < 0.001) and nt 94G>A (P-value = 0.007), were also associated with a significant increase in risk for cervical cancer. Two substitutions found to confer a lower risk for cervical cancer were nt 7911A>C (P-value = 0.007) and nt 19T>C (P-value = 0.008), both of which located at LCR. No significant associations between HPV-52 E7 or L1 variants and cervical cancer development were observed. Further studies are needed to confirm these findings, and in-depth investigations into the virological and functional implications of HPV-52 sequence variations are warranted. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhang, Chuqing. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 124-137). / Abstracts also in Chinese. / Abstract --- p.i / Acknowledgements --- p.v / Table of contents --- p.vii / List of Figures --- p.ix / List of Tables --- p.x / Abbreviations --- p.xii / Chapter Chapter One --- Introduction --- p.1 / Chapter 1.1 --- History of Human Papillomavirus --- p.2 / Chapter 1.2 --- Biology of Human Papillomavirus --- p.4 / Chapter 1.2.1 --- Genome structure --- p.4 / Chapter 1.2.2 --- Protein function --- p.6 / Chapter 1.2.3 --- Latent and lytic life cycle --- p.9 / Chapter 1.2.4 --- Classification --- p.10 / Chapter 1.3 --- Epidemiology of Human Papillomavirus --- p.14 / Chapter 1.3.1 --- Global burden --- p.14 / Chapter 1.3.2 --- Transmission --- p.18 / Chapter 1.3.3 --- Clinical course --- p.19 / Chapter 1.3.4 --- Prevention --- p.23 / Chapter 1.4 --- Human Papillomavirus Type 52 --- p.25 / Chapter 1.5 --- Objectives --- p.26 / Chapter Chapter Two --- Materials and Methods --- p.27 / Chapter 2.1 --- Study Design --- p.28 / Chapter 2.2 --- Study population --- p.29 / Chapter 2.3 --- DNA extraction --- p.31 / Chapter 2.4 --- Polymerase chain reaction --- p.32 / Chapter 2.4.1 --- Long-fragment PCR approach --- p.33 / Chapter 2.4.2 --- Short-fragment PCR approach --- p.40 / Chapter 2.4.3 --- Purification of PCR products --- p.46 / Chapter 2.5 --- Nucleotide sequencing --- p.47 / Chapter 2.6 --- Data analysis --- p.48 / Chapter 2.6.1 --- Phylogenetic analysis --- p.48 / Chapter 2.6.2 --- Statistical analysis --- p.49 / Chapter Chapter Three --- Results --- p.50 / Chapter 3.1 --- Phylogeny of HPV-52 --- p.53 / Chapter 3.1.1 --- Concatenated sequence of L1-LCR-E6-E7 --- p.53 / Chapter 3.1.2 --- E6 gene --- p.56 / Chapter 3.1.3 --- E7 gene --- p.59 / Chapter 3.1.4 --- L1 gene --- p.62 / Chapter 3.1.5 --- Long control region --- p.67 / Chapter 3.2 --- Nucleotide sequence variation of HPV-52 --- p.70 / Chapter 3.2.1 --- E6 gene --- p.70 / Chapter 3.2.2 --- E7 gene --- p.73 / Chapter 3.2.3 --- L1 gene --- p.75 / Chapter 3.2.4 --- Long control region --- p.81 / Chapter 3.3 --- Geographical distribution of HPV-52 variants --- p.86 / Chapter 3.4 --- Risk association of HPV-52 variants --- p.96 / Chapter Chapter Four --- Discussion --- p.105 / Chapter 4.1 --- Strengths and weaknesses --- p.107 / Chapter 4.2 --- Phylogeny of HPV-52 variants --- p.109 / Chapter 4.2.1 --- Variant lineage classification system of HPV-52 --- p.109 / Chapter 4.2.2 --- Sequence variability of HPV-52 --- p.110 / Chapter 4.2.3 --- Evolutionary pressure on HPV-52 --- p.111 / Chapter 4.3 --- Nucleotide sequence variations of HPV-52 --- p.113 / Chapter 4.3.1 --- E6 gene --- p.113 / Chapter 4.3.2 --- E7 gene --- p.114 / Chapter 4.3.3 --- L1 gene --- p.116 / Chapter 4.3.4 --- Long control region --- p.117 / Chapter 4.4 --- Conclusions --- p.121 / References --- p.124 / Appendices --- p.138

Muitos pacientes submetidos à tireoidectomia por Carcinoma Papilífero da Tireoide (CPT) têm doença linfonodal subclínica no momento da cirurgia. A mutação BRAF T17799A (V600E) é um evento comum no CPT e alguns estudos demonstram correlação entre a mutação e características de maior agressividade tumoral, incluindo a presença de metástases linfonodais. O esvaziamento eletivo do compartimento central ganha aceitação, uma vez que alguns estudos evidenciam que a presença de metástases linfonodais aumenta o risco de recidiva e mortalidade. Devido ao grande potencial de complicações do esvaziamento do compartimento central, o objetivo deste trabalho foi avaliar a associação entre a presença da mutação BRAF T17799A (V600E), a presença de metástases linfonodais e fatores clínicos e histopatológicos de pior prognóstico. Métodos: 51 casos consecutivos de pacientes com CPT foram submetidos à tireoidectomia total e ao esvaziamento eletivo ou terapêutico do compartimento central. Em todos os pacientes foi pesquisada a mutação BRAF T17799A (V600E) no tecido tireoidiano com Carcinoma Papilífero de Tireoide. Resultados: Cinquenta e quatro por cento (54,9%) dos pacientes apresentaram metástases linfonodais. Seis pacientes apresentaram metástases laterais confirmadas por punção aspirativa por agulha fina no pré-operatório e 22 pacientes (43%) apresentaram metástases não detectadas no pré ou no intra operatório A mutação BRAF T17799A (V600E) foi encontrada em 15 pacientes portadores de CPT (29,4%). A presença da mutação não teve associação estatisticamente significante para sexo, idade, tamanho do tumor, extensão extratireoidiana, multicentricidade, embolização angiolinfática e metástases linfonodais. As metástases linfonodais se associaram à multifocalidade (p = 0,005) e invasão angiolinfática (p = 0,003) na análise univariada. Conclusão: A presença da mutação BRAF T17799A (V600E) não se associou à metástases linfonodais em nosso estudo. A multifocalidade e a detecção de invasão angiolinfática no CPT foram os fatores mais importantes na predição de metástases linfonodais / Background: Many patients undergoing thyroidectomy for Papillary Thyroid Carcinoma (PTC) have subclinical node disease at the time of surgery. The BRAF T17799A (V600E) mutation is a common event in PTC and some studies have demonstrated a correlation between the mutation and aggressive characteristics including lymph node metastasis. Prophylactic Central Node Dissection (CND) is gaining acceptance in the treatment of PTC as studies have shown nodal disease increases local recurrence and may alter mortality. Given the potential complications of CND, the aim of this study was to determine the correlation among BRAF mutation, lymph node metastasis and clinical and histopathological factors of worse prognosis. Methods: A total of 51 consecutive cases of patients with PTC underwent total thyroidectomy and routine prophylactic (CND) or therapeutic neck dissection when metastases were found. All patients were tested for the BRAF mutation. Results: Overall, positive lymph nodes were found in Fifty four per cent9% of patients. Six patients had lateral metastases confirmed by fine needle aspirative cytology and 22 patients (43%) had occult metastases. The BRAF mutation was found in 15 patients (29.4%). BRAF was not correlated with sex, age, size of tumor, multifocality, extrathyroid extension or lymph node metastases. Lymph node metastases were correlated with multifocality (p = 0.005) and angiolymphatic invasion (p = 0.003) in univariate. Conclusions: The BRAF mutation was not correlated with lymph node metastases in our study. Multifocality and angiolymphatic invasion were important factors for predicting lymph node metastases

O objetivo deste trabalho foi estudar a expressão protéica de mdm2 e avaliar a sua relação com alguns aspectos anatomopatológicos, visando também identificar fatores prognósticos no que diz respeito à sobrevida livre de recidiva local (SLRL), sobrevida livre de metástase (SLM) e sobrevida global (SG), em pacientes portadores de lipossarcoma primário de extremidades. Vinte e cinco entre 50 pacientes admitidos no Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo – IOT/HC/FMUSP, entre 1968 e 2004, foram eleitos para o estudo. As probabilidades de sobrevida acumuladas foram feitas pela técnica de Kaplan-Meier e as curvas de sobrevida comparadas pelo teste de Log Rank. A validade estatística foi estabelecida para valores de p<0,05. As associações entre os índices positivo ou negativo para o mdm2 com outras variáveis foram feitas utilizando-se o teste exato de Fischer. A expressão imunoistoquímica da proteína mdm2 não foi considerada de valor prognóstico em nenhuma das sobrevidas estudadas (SLRL, SLM ou SG). Os fatores adversos que influenciaram o risco de recidiva local na análise univariada foram: o gênero masculino (p = 0,023), subtipo histológico pleomórfico (p = 0,027) e alto grau histológico (p=0,007). Em relação a SLM a idade inferior a 50 anos (p = 0,040), o gênero masculino (p = 0,040), o subtipo pleomórfico (p < 0,001), o alto grau histológico (p = 0,003) tiveram um pior prognóstico. Os fatores adversos para SG foram: idade inferior a 50 anos (p = 0,040); o gênero masculino (p = 0,040); o subtipo pleomórfico (p < 0,001) e o alto grau histológico (p = 0,003). / The purpose of this was to study the expression by imunohistochemistry of mdm2 and your correlation with anatomopathological selected variables, aiming at identifying prognostic factors concerning to local recurrence free survival (LRFS), metastases free survival (MFS) and overall survival (OS) in patients with liposarcomas primary extremities. This study included 25 patients registred in the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Brazil, from 1968 to 2004. The accumulated survival probabilities were calculated by Kaplan-Meier method and survival curves were compared using the logrank test. Statistical significance was defined as a p value less than 0,05. Associations between expression of mdm2 and other variables were analyzed using Fischer’s exact test. The expression by imunohistochemistry of mdm2 was not significant factor for LRFS, MFS or OS. The adverse factors for LRFS in univariate analysis were male gender (p = 0,023), pleomorfic histologic subtypes (p = 0,027) and high grade tumor (p = 0,007). For MFS age < 50 years (p = 0,040), male gender (p = 0,040), pleomorfic histologic subtypes (p < 0,001) and high grade tumor (p = 0,003) had worse prognostic. Negative prognostic factors for OS were age < 50 years (p = 0,040), male gender (p = 0,040), pleomorfic histologic subtypes (p < 0,001) and high grade tumor (p = 0,003).

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references. Also available online.

Interactions between the retinoic acid receptor alpha (RARalpha) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In acute promyelocytic leukemia (APL), RARalpha is fused with the promyelocytic leukemia (PML) gene, resulting in the expression of the fusion protein PML/RARalpha. Here, I report that topoisomerase II beta (topoIIbeta) associates with and negatively modulates PML/RARalpha and RARalpha transcriptional activity, and increased levels and association of topoIIbeta cause resistance to retinoic acid (RA) in APL cell lines. Knock down of topoIIbeta was able to overcome resistance by permitting RA-induced differentiation and increased RA-gene expression. Overexpression of topoIIbeta, in clones from an RA-sensitive cell line, conferred resistance by a reduction in RA-induced expression of target genes and differentiation. Chromatin immunoprecipitation assays indicate that topoIIbeta is bound to an RA-response element, and inhibition of topoIIbeta causes hyper-acetylation of histone 3 at lysine 9 and activation of transcription. These results identify a novel mechanism of resistance in APL and provide further insights to the role of topoIIbeta in gene regulation and differentiation. / Studies to determine the mechanism by which topoIIbeta protein is regulated found that levels of protein kinase C delta (PKCdelta) correlated with topoIIbeta protein expression. Moreover, activation of PKCdelta, by RA or PMA, led to an increase of topoIIbeta protein levels. Most notably, in NB4-MR2 cells, we observed increased phosphorylation levels of threonine 505 on PKCdelta, a marker of activation. Inhibition of PKCdelta was able to overcome the topoIIbeta repressive effects on RA-target genes. In addition, the combination of RA and PKCdelta inhibition led to increased expression of the granulocytic marker, CD11c, in NB4 and NB4-MR2 cells. These results suggest that PKCdelta regulates topoIIbeta expression, and a constitutively active PKCdelta in the NB4-MR2 cell line leads to overexpression of topoIIbeta. / In conclusion, these studies demonstrate that topoIIbeta associates with RARalpha, binds to RAREs and plays a critical role in RA dependent transcriptional regulation and granulocytic differentiation. In addition, I show that topoIIbeta overexpression leads to RA resistance and provide evidence that topoIIbeta protein levels are regulated via a mechanism involving the PKCdelta pathway. This work has contributed to an enhanced understanding of the role of topoIIbeta in gene regulation and brings novel perspectives in the treatment of RA-resistance in APL.

Breast cancer is a heterogeneous disease comprised of distinct biological entities that correlate with diverse clinical outcomes. Gene expression profiling has divided this heterogeneity into luminal, ERBB2+ and basal molecular subtypes. Basal breast cancers are difficult to treat as they lack expression of candidates suitable for targeted therapies and are associated with poor outcome. / Elevated protein level of the hepatocyte growth factor receptor, MET, is observed in 20% of human breast cancers and correlates with poor prognosis. However, the role of MET in mammary tumorigenesis is poorly understood. To address this, we generated a murine model that expresses weakly oncogenic mutants of Met (Metmt) in the mammary epithelium under the transcriptional control of the mouse mammary tumor virus promoter. We demonstrate that Metmt induces mammary carcinomas with diverse phenotypes and used gene expression microarrays to elucidate gene expression changes induced by Met. Since mammary tumors contained variable contents of epithelium and stroma, we used laser capture microdissection to procure epithelial cells for microarray analysis. Based on immunohistochemistry and expression profiling, we show that Metmt produces tumors with luminal or basal characteristics. From hierarchical clustering, Metmt-induced basal tumors clustered with murine models that share features of epithelial to mesenchymal transition and human basal breast cancers. Moreover, Metmt basal tumors clustered with human basal breast cancer. The status of MET among the human breast cancer subtypes has not previously been addressed. We demonstrate that MET levels are variable across molecular subtypes but show elevation in the basal subtype and correlates with poor outcome. We used a candidate gene approach derived from microarray data to gain an understanding of signals required for Met-dependent tumorigenesis. We investigated Nck adaptor proteins and demonstrate a role for Nck in cell motility and actin dynamics of Met-dependent breast carcinoma cells and show elevated expression in human basal breast cancers. By generating a unique mouse model in which Met is expressed in mammary epithelia, with the examination of MET levels in human breast cancer, we have established a novel link between MET and basal breast cancer. This work identifies poor outcome basal breast cancers that may benefit from anti-MET therapies.

The altered protein expression and activity of receptor tyrosine kinases (TK) are implicated in the progression of various types of cancers. One such dysfunction is the overexpression of the epidermal growth factor receptor (EGFR) that correlates with aggressive tumor progression and poor prognosis. On the other hand, c-Src non-receptor tyrosine kinase is overexpressed and activated in a large number of human malignancies and has been strongly linked to progression to distant metastases. c-Src-induced phosphorylation of EGFR is required for EGF-mediated mitogenesis, tumorigenesis and tumour invasiveness. Thus we surmised that molecules termed "combi-molecules" designed to block both EGFR and c-Src should not only possess significant growth inhibitory potency but also strong anti-invasive properties. In this thesis, we utilized molecular modeling to design molecules containing two moieties: one that straddles the structure of the known Src inhibitor PP2 and the other that mimics the backbone of Iressa, a potent EGFR inhibitor. Of all the molecules synthesized, only SB163 containing the longest spacer between the two moieties was capable of inducing a dose dependent inhibition of both Src and EGFR. More importantly, SB163 blocked cell motility in the wound healing assay and showed significantly greater anti-invasive activity than a PP2+Iressa combination. The observation that SB163 was a less potent EGFR or Src inhibitor than Iressa and PP2 suggests that its superior potency when compared with the PP2+ Iressa combination may be at least partially attributed to mechanisms other than EGFR or Src blockade. This was also corroborated by the fact that SB163, despite its significant bulkiness (>700) could induce dose dependent inhibition of other kinase such PDFGR and Abl. The results in toto suggest that conferring multiple kinase targeting properties to single molecules can lead to highly anti-proliferative and anti-invasive agents. Traditionally, multi-kinase targeted molecules were discovered serendipitously through multi-kinase testing. Here we initiated a more rational approach to the design of single multi-targeted molecules. Cancer being a complex disease driven by tumours characterized by multiple disordered signaling pathways, this approach may well represent a novel avenue in the therapy of refractory malignancies.

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 82 pages. Includes vita. Includes bibliographical references.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.