Background: The systemic immune-inflammation index based on peripheral neutrophil, lymphocyte, and platelet counts has shown a prognostic impact in several malignancies. The aim of this study was to determine the prognostic role of systemic immune-inflammation index in patients with pancreatic ductal adenocarcinoma undergoing resection. Methods: Consecutive patients who underwent surgical resection at the department of surgery at the Medical University of Vienna between 1995 and 2014 were included into this study. The systemic immune-inflammation index was calculated by the formula platelet*neutrophil/lymphocyte. Optimal cutoffs were determined using Youden's index. Uni-and multivariate analyses were calculated by the Cox proportional hazard regression model for overall survival. Results Three hundred twenty-one patients were included in this study. Clinical data was achieved from a prospective patient database. In univariate survival analysis, elevated systemic immune-inflammation index was found to be significantly associated with shortened patients' overall survival (p = 0.007). In multivariate survival analysis, systemic immune-inflammation index remained an independent prognostic factor for overall survival (p = 0.004). No statistical significance could be found for platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in multivariate analysis. Furthermore, area under the curve analysis showed a higher prognostic significance for systemic immune-inflammation index, compared to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio. Conclusion A high systemic immune-inflammation index is an independent, preoperative available prognostic factor in patients with resectable pancreatic ductal adenocarcinoma and is superior to platelet to lymphocyte ratio and neutrophil to lymphocyte ratio for predicting overall survival in pancreatic ductal adenocarcinoma patients.

The UK has experienced an increase in the incidence of oesophageal adenocarcinoma (OAC) in recent years. The prognosis for patients with OAC remains poor with currently available treatments prompting a search for alternative ‘chemopreventive’ treatments that inhibit oesophageal carcinogenesis. Both non-steroidal anti-inflammatory drugs (NSAIDS) and flavonoids are associated with a significant risk reduction for developing OAC in epidemiological studies. The aim of this study was to validate Levrat’s surgical model of OAC in the rat, and assess the chemopreventive effects of the NSAID aspirin, and the flavonoid quercetin on the development of OAC in the validated rat model. METHODS: Levrat’s model was validated in a time course experiment. Morphological and molecular events occurring in the distal oesophagus during disease progression were determined and compared to human disease. The effect of aspirin and quercetin on disease initiation and progression was determined by commencing treatment either before the onset of reflux, or 4-weeks afterwards. The incidence of Barrett’s oesophagus (BO) and OAC within each group was determined, along with methylation levels of the ESR-1, p16 and HPP1 gene promoter regions. RESULTS: The morphological and molecular changes in the distal oesophagus of the rat model are broadly consistent with those reported in human disease. The incidence of OAC was significantly lower in aspirin treated rats. A non-significant reduction in incidence of OAC was observed with quercetin treatment. Timing of treatment with regard to onset of reflux had no significant effect on OAC development in either treatment group. Neither treatment significantly effected methylation levels within the gene promoters examined. CONCLUSION: Use of Levrat’s model as a model of human OAC seems justified. Aspirin inhibits development of oesophageal adenocarcinoma induced by reflux in this rat model. No additional reduction in cancer incidence is observed if treatment is commenced prior to inception of reflux disease.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by an intense desmoplastic stromal response that can comprise 60 to 80% of tumour volume and has been implicated to be a factor in promoting tumour invasiveness and the poor prognosis associated with this cancer type. It is now well established that pancreatic stellate cells, which are vitamin A storing cells found in the periacinar spaces of the stroma in the normal gland, are primarily responsible for this desmoplastic reaction. Studying the interaction between stellate cells and cancer cells could provide for a better understanding of the disease process. During the evolution of PDAC, the stromal proportion increases from 4% in the normal gland to up to 80%. We hypothesised that there is an optimal proportion of stellate cells and cancer cells that modulates tumour behaviour and we attempted to dissect out this probable ‘tipping point’ for stromal composition upon cancer cell behaviour using a well-established in vitro organotypic culture model of pancreatic cancer. The cancer cell-stromal cell interaction led to extra-cellular matrix contraction and stiffening; and an increase in cancer cell number. The stromal stellate cells conferred a pro-survival and pro-invasive effect on cancer cells which was most pronounced at a stellate cell proportion of 0.66-0.83. The expression of key molecules involved in EMT and metastasis such as E-Cadherin and β-catenin showed a reduction and this was found to be most significant again at a stellate cell proportion of 0.66-0.83. Stellate cells altered the genetic profile of cancer cells leading to differential expression of genes involved in key cellular pathways such as cell-cycle and proliferation, cell movement and death, cell-cell signalling, and inflammatory response. qRT-PCR confirmed the differential expression of the top differentially expressed genes and protein validation by immunofluorescence staining using PIGR as a candidate molecule confirmed the experimental findings in human PDAC specimens. This study demonstrates that the progressive accumulation of desmoplastic stromal cells has a tumour progressive (pro-survival, pro-invasive) effect on cancer cells in addition to stiffening (contraction) of the extracellular matrix (maximum effect when the stromal cell proportion is 60-80%). This is mediated through a number of signalling cascades and molecular targets. Dampening this tumour-promoting interaction between cancer and stromal cells by ‘multi-targeting’ agents may allow traditional chemo- and/or radiotherapy to be effective.

Introduction: Polymeric immunoglobulin receptor (pIgR) traffics Immunoglobulins (IgA and IgM) through epithelial cells in normal mucosae but neither are expressed in the normal pancreas. Recent work has demonstrated pIgR to be upregulated in hepatocellular carcinoma, even though it is not expressed in normal liver cells. High pIgR levels are associated with poor survival and distant metastases for a number of cancers such as nasopharyngeal cancers, lung and oesophageal cancers. Recent work from our laboratory suggested pIgR may be upregulated in pancreatic ductal adenocarcinoma (PDAC). My aim was to assess pIgR's role in PDAC by interrogating human PDAC tissue samples as well using cell biology experimental tools. Methods: pIgR expression was manipulated (siRNA and shRNA) in cell lines to evaluate its subsequent effect on cell behaviour in 2D assays as well as 3D organotypics models. Tissue Microarrays of patients with PDAC were analysed after pIgR, αSMA, E-Cadherin and Picrosirius Red staining to assess their role as a combined bio-marker panel. Results: Cytokines such as interleukin 4 (IL4) and Tumour Necrosis Factor (TNFα) could not modulate pIgR expression in PDAC cell lines despite this effect being seen in other studies using colorectal and nasopharyngeal cancer cell lines. Downregulation in pIgR expression in Capan1 cell line resulted in reduction of cellular proliferation (n= 3, P < 0.05, Friedman test), adhesion (n= 3, P < 0.05, Kruskal-Wallis) and migration (n= 3, P < 0.05, Kruskal-Wallis). In 3D organotypic models, pIgR downregulation resulted in reduced cancer cell invasion (n= 9, P < 0.05, Kruskal- Wallis) and diminished contraction of gels (n= 9, P < 0.05, Kruskal-Wallis). In human PDAC, decreased E-cadherin expression correlates with increased pIgR expression through pancreatic intra-epithelial neoplasia (PanIN) progression. There was no IgA expression in PDAC. pIgR expression had no clinical correlation with routine prognostic measures such as differentiation, lymph node metastasis (n= 88, P=0.5012, Kruskal-Wallis). Even in combination with stromal indices (α-smooth muscle action (SMA) and Picrosirius red), low pIgR scores had no statistically significant impact on prognosis but had a trend towards better survival (n= 88, P=0.2791, Mann-Whitney U test). Conclusion: pIgR may be involved in progression from pre-neoplastic lesions such as PanIN to PDAC. pIgR may have a biological impact on cellular motility and invasion due to yet to be deciphered signalling cascades with marked effect on cellular phenotype. Careful analysis is required to study the impact of pIgR on prognostic impact bearing in mind the histological sub-types of pancreatic cancer.

O adenocarcinoma ductal pancreático (ADP) é uma doença altamente letal e agressiva. Alteração no perfil de acetilação das histonas envolvendo desacetilases de histonas (HDAC), assim como modificações da expressão de miRNAs podem levar ao desenvolvimento tumoral. Neste estudo, foi avaliada a expressão das HDAC1, HDAC2, HDAC3 e HDAC7 em ADP e amostras de tecido pancreático não tumoral (TN) usando análises experimentais e de banco de dados. Os níveis de expressão foram correlacionados com características clínico-patológicas dos pacientes e foi realizada uma investigação in silico de miRNAs reguladores de efeito das HDACs. Os níveis de expressão das HDACs foram avaliadas por qRT-PCR a partir de 25 amostras de ADP e 23 amostras de TN e a análise da expressão diferencial (ED) e correlação entre HDACs e miRNAs em ADP foi realizada utilizando perfis de expressão de seis microarranjos do Gene Expression Omnibus. Potenciais relações miRNA-HDACs foram coletadas em bases de dados de interação de miRNAs. Um valor de P<0,05 foi considerado estatisticamente significativo. Encontramos expressão reduzida em ADP comparado com TN para todas as HDACs analisadas, com P<0,05 para HDAC1, 2 e 3. Entretanto, os fold-changes foram muito baixos e provavelmente sem relevância biológica, e a expressão da HDAC2 e HDAC7 foi correlacionada com a idade ao diagnóstico. Nenhuma outra correlação entre a expressão das HDACs e características clínico-patológicas foi identificada. Análises de ED sugeriram significativa superexpressão das HDAC1, 2 e 7 e subexpressão da HDAC3, contudo todas apresentaram fold-changes pequenos. As análises dos bancos de dados identificaram 728 miRNAs como reguladores das HDACs. Interseções entre os conjuntos de miRNAs (GSE41369 e GSE43796) e aqueles recuperados da análise de expressão diferencial indicaram cinco miRNAs que influenciam a HDAC1 (miR-188-5p, miR-539, miR-708, miR -4269 e miR-3616-3p) e três que influenciam a HDAC2 (miR-4307, miR-944 e miR-195). A expressão das HDACs provavelmente não é um biomarcador de prognóstico robusto para o ADP, uma vez que a expressão diferencial entre os grupos é sutil. Ainda, este e estudos anteriores indicam nenhuma ou pouca associação entre a expressão HDACs e características clínico-patológicas relacionadas com o prognóstico. Finalmente, miRNAs provavelmente não estão exercendo um papel central na regulação da HDACs no ADP. / Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and aggressive disease. The disruption of histone acetylation through histones deacetylases (HDACs) and expression regulation by miRNAs can lead to tumor development. In this study we assessed HDAC1, HDAC2, HDAC3 and HDAC7 expression in PDAC and non-tumoral tissue (NT) samples using experimental and databases analysis, correlated their expression levels with clinical and pathological features in patients and performed in silico investigation of HDACs regulation by miRNAs. Expression levels of HDACs were measured by qRT-PCR from 25 PDAC and 23 NT. An analysis of differential expression (DE) and correlation of HDACs and miRNAs in PDAC was performed using six Gene Expression Omnibus microarray datasets. Potential miRNA-HDACs relationships were collected from miRNA interaction databases. A P<0.05 was considered statistically significant. We found reduced expression in PDAC compared with NT for HDAC1, HDAC2 and HDAC3, with P<0.05. Expression levels of HDAC7 did not significantly differ between groups. However, fold-changes were very small and probably not biologically relevant. Only HDAC2 and HDAC7 were associated with age at diagnosis and no other associations between HDAC expression and clinical features were identified. DE analysis suggested significant up-regulation of HDAC1, HDAC2 and HDAC7, and down-regulation of HDAC3, albeit all of them associated with small fold changes. Databases analysis identified 728 miRNAs that could be HDACs regulators. Intersections among the set of miRNAs found in differential expression analysis of GSE41369 and GSE43796 and those retrieved from target prediction identified five miRNAs targeting HDAC1 (miR-188-5p, miR-539, miR-708, miR-4269 and miR-3616-3p) and three targeting HDAC2 (miR-4307, miR-944 and miR-195). HDACs expression is likely not a robust prognostic biomarker in PDAC since differential expression between groups is subtle. Also, this and previous studies indicate no or only very few associations between HDACs expression and clinicopathological features related to prognosis. Finally, miRNAs are probably not exerting a central role in HDAC regulation in PDAC.

Made available in DSpace on 2015-04-14T13:34:44Z (GMT). No. of bitstreams: 1 347982.pdf: 1600667 bytes, checksum: 2a60ad3de906ac67f5a05683369e9a69 (MD5) Previous issue date: 2006-06-07 / A import?ncia da intera??o entre o mecanismo de coagula??o e o c?ncer ? reconhecida desde as descri??es pioneiras de Trousseau. Mais recentemente, estudos demonstraram a import?ncia do fator tecidual, uma prote?na de membrana celular ligada ao desencadeamento da cascata da coagula??o, na progress?o de neoplasias malignas atrav?s da estimula??o do processo de angiog?nese. Realizamos marca??o imunoistoqu?mica para o fator tecidual em 43 adenocarcinomas colo-retais de pacientes submetidos a tratamento cir?rgico no Servi?o de Coloproctologia do HSL-PUCRS e comparamos a intensidade da sua express?o com a densidade microvascular, crit?rios de estadiamento, idade, sexo e sobrevida geral. Oitenta e tr?s por cento dos tumores apresentaram alta express?o do fator tecidual, havendo uma rela??o estatisticamente significativa entre esta e a maior densidade microvascular (p=0,02). Observamos tamb?m que os pacientes com alta express?o do fator tecidual apresentavam uma m?dia de idade significativamente maior do que a dos pacientes com baixa express?o desta prote?na (p<0,01). Em conclus?o, a elevada intensidade de marca??o imunoistoqu?mica para o fator tecidual se relacionou com uma m?dia de densidade microvascular mais elevada e com pacientes mais idosos quando comparados aos casos com baixa express?o desta prote?na.

O câncer de pulmão é a neoplasia maligna mais insidiosa da oncologia, sendo responsável pelo maior número de mortes relacionadas ao câncer no mundo. Oitenta e cinco por cento dos casos de câncer de pulmão são de não-pequenas células (CPNPC), onde sua maioria é adenocarcinoma. Apesar dos progressos nas pesquisas em câncer, o prognóstico de pacientes em estágios avançados permanece ruim, portanto faz-se necessária o desenvolvimento de novas abordagens terapêuticas. Nesse trabalho, focamos no metabolismo energético tumoral, o qual apresenta alto consumo de glicose e liberação de lactato mesmo na presença de oxigênio, o chamado Efeito Warburg. Outras vias metabólicas também encontram-se alteradas, processo conhecido como reprogramação metabólica. Dessa forma, o objetivo desse trabalho é buscar possíveis marcadores tumorais e alvos terapêuticos envolvidos no metabolismo energético, através de uma abordagem que começa na bioinformática, de forma a prospectar candidatos a partir de uma vasta gama de genes envolvidos com o metabolismo. Foram selecionados os genes IDH1, LDHA e PYGB a partir de uma análise de enriquecimento gênico, os quais foram submetidos a análises de sobrevida em bancos de dados de microarranjo. Em seguida, o nível de expressão das proteínas IDH1 e LDHA foi avaliado por imunohistoquímica em uma coorte clínica, onde pudemos observar um aumento na expressão de IDH1 em tumores em relação a tecidos pulmonares sadios. Ainda, em modelo celular, observamos que ambas as proteínas estavam aumentadas em células tumorais de adenocarcinoma pulmonar em relação a células sadias de pulmão. Ao combinar o inibidor de LDHA, oxamato, com cisplatina na linhagem de adenocarcinoma pulmonar A549, foi observado uma interação de sinergismo e, na linhagem pulmonar sadia NHBE, foi observado um antagonismo, de forma que essa abordagem se mostra promissora na terapêutica. Já ao combinar o inibidor de IDH1, oxalomalato, com cisplatina na linhagem A549, foi observado um antagonismo. Assim, esse estudo demonstrou um possível papel de biomarcador para adenocarcinoma pulmonar para a enzima IDH1 e um possível papel terapêutico para a enzima LDHA.

O objetivo deste estudo foi avaliar os parâmetros farmacocinéticos da talidomida em pacientes com tumores sólidos refratários incluídos em estudo de fase II em nossa Instituição. Foram incluídos 14 pacientes, sendo 5 com diagnóstico de adenocarcinoma de reto, 4 com adenocarcinoma de cólon, 4 com melanoma e 1 com adenocarcinoma de pâncreas. Todos os pacientes foram previamente tratados, 14 com cirurgia, 11 com quimioterapia, 5 com radioterapia e 1 com imunoterapia. Os pacientes foram inicialmente tratados com talidomida 200 mg/dia, com um aumento de dose de 200mg a cada duas semanas, até atingir a dose máxima de 800 mg/dia. Treze pacientes atingiram o nível de 400mg/dia, 9 pacientes os níveis de 600mg/dia e apenas 5 pacientes atingiram 800mg/dia. A farmacocinética foi caracterizada em oito pacientes no nível de dose de 200 mg/dia. Todos os 14 pacientes incluídos foram avaliados quanto ao perfil de toxicidade e resposta antitumoral. A talidomida foi bem tolerada, sendo os principais efeitos colaterais a sonolência, a tontura, a xerostomia e a constipação. Não foram observadas respostas tumorais objetivas. Para avaliar os parâmetros farmacocinéticos da talidomida foram coletadas amostras de sangue imediatamente antes da administração da droga, 1h, 2h, 2,5h, 3h, 3,5h, 4h, 5h, 7h e 24h após a administração da primeira dose de talidomida de 200mg. A determinação das concentrações e parâmetros farmacocinéticos da talidomida nestas amostras foi realizada por cromatografia líquida de alta performance. A curva de decaimento das concentrações plasmáticas obedeceu a um modelo farmacocinético monocompartimental. A média dos principais parâmetros farmacocinéticos estudados foi: Cmax 1,48 ± 0,56μg/ml, Tmax 4,4± 0,5h, ASC 17,7±8,4μg x h/mL e t½ 6,5±3,0 hs. O autor pode concluir que os parâmetros farmacocinéticos da talidomida estudados nestes pacientes foram semelhantes àqueles descritos anteriormente em voluntários sadios, pacientes com HIV, hanseníase ou adenocarcinoma de próstata. / The objective of this study was to evaluate the pharmacokinetic parameters of thalidomide in patients with refractory solid tumors included in phase study II in our institution. Fourteen patients were included of whom 5 were diagnosed with rectum adenocarcinoma, 4 with colon adenocarcinoma, 4 with melanoma and 1 with pancreas adenocarcinoma. All the patients had been treated previously, 14 with surgery, 11 with chemotherapy, 5 with radiotherapy and 1 with immunotherapy. The patients were treated initially with 200mg/day thalidomide, with a dosage increase of 200mg every two weeks, reaching the maximum dose of 800mg/day. Thirteen patients reached the level of 400mg/day, 9 patients the level of 600mg/day and 5 patients reached 800mg/day. Pharmacokinetics took place in eight patients at the dosage level of 200 mg/day. All 14 patients were evaluated on the toxicities profile and antitumor activity. Thalidomide was well tolerated, the main collateral effects being the drowsiness, dizziness, mouth dryness and constipation. No objective responses were observed. To evaluate the pharmacokinetic parameters of thalidomide samples of blood were collected, 1:00, 2:00, 2.5, 3:00, 3.5, 4:00, 5:00, 7:00 and 24:00 hours after the administration of the first dose of 200mg thalidomide. The determination of the concentrations and pharmacokinetic parameters of thalidomide in these samples were achieved by high-performance liquid chromatography. A one-compartment pharmacokinetic model best fit the concentrations of thalidomide in plasma. The mean of the main studied pharmacokinetic parameters was: Cmax 1.48 ± 0.56mg/ml, Tmax 4.4± 0.5h, ASC 17.7±8.4mg x h/ml, t½ 6.5±3.0 hs. The pharmacokinetic parameters of thalidomide studied in these patients were similar to those described in healthy patients, those with HIV, Hansen’s disease or prostate adenocarcinoma.

O adenocarcinoma de estômago foi a principal causa de morte por neoplasia maligna no mundo durante grande parte do século XX e atualmente é superado somente pelas neoplasias epiteliais malignas de pulmão. Cerca de 750.000 novos casos são diagnosticados anualmente. Apresenta grande variação geográfica, sendo suas maiores incidências encontradas no Japão, América do Sul, Europa Oriental e Oriente Médio. É duas vezes mais freqüente em homens do que em mulheres; é pouco comum antes dos 40 anos e atinge sua maior incidência por volta da sétima década de vida. No Brasil as estimativas para o ano de 2005 apontavam para aproximadamente 23 mil casos novos e 11 mil óbitos. O único tratamento potencialmente curativo é a ressecção completa, macro e microscópica, de toda neoplasia. Mesmo após gastrectomia curativa, a recidiva, regional ou à distância, pode ocorrer em 80% dos casos. Esforços para melhorar estes resultados têm se focalizado no desenvolvimento de terapias pré e pós-operatórias mais efetivas.O oncogene p16 é conhecido por estar implicado na patogênese de muitos tumores humanos e também na regulação do crescimento celular normal, juntamente com as ciclinas, os complexos tirosinoquinases e os fatores de crescimento e transformação tumoral, entre eles o TGF-alfa e beta e os fatores de crescimento derivados de plaquetas (PDGF) e seus receptores (PDGFR alfa e beta). A perda de expressão do p16 no adenocarcinoma gástrico tem sido amplamente estudada. O PDGFR tem sido encontrado ativado e mutado nos tumores gástricos estromais em que o c-KIT, o marcador mais comumente encontrado, está em sua forma selvagem. Os receptores PDGF atuam sobre células de origem estromal e não se expressam em células epiteliais em condições fisiológicas normais. . Isoladamente, o PGDF-beta e o seu receptor ainda não foram objetivamente estudados nem quanto à expressão nem quanto à resposta aos inibidores do crescimento celular no tecido gástrico tumoral quenão de origem estromal.O objetivo deste estudo foi determinar a expressão imunohistoquímica do p16 e do PDGFR-beta no adenocarcinoma gástrico. Foram avaliados no estudo 36 pacientes submetidos à cirurgia por adenocarcinoma de estômago entre os anos de 1998 e 2002 no Complexo Hospitalar Santa Casa de Porto Alegre. As variáveis estudadas foram idade, sexo, localização do tumor, tamanho do tumor, número de linfonodos ressecados, número de linfonodos metastáticos, tipo histológico, tipo de cirurgia e estadiamento patológico (TNM). Não foi detectada expressão do PDGFRbeta em nenhuma das lâminas estudas. O p16 apresentou expressão menor que 10% em 89% dos casos e menor que 1% em 78% dos casos. Não foi detectada correlação entre a perda de expressão do p16 e as variáveis estudadas. / Gastric adenocarcinoma has been the main cause of cancer death during most of the twentieth century, now overcame by lung cancer. Annually 750,000 new cases are diagnosed. Great geographic variations are seen and highest incidences can be found in Japan, South America, Eastern Europe and Middle East. It is twice as frequent in men as in women, has o low incidence before the fourth decade with a peak incidence in the seventh decade. In Brazil 23,000 new cases and 11,000 deaths are estimated to 2005. Complete resection of all gross and microscopic disease is the only potentially curative treatment. However, disease recurs in 80% of patients even after curative resection. Efforts to improve these results concentrate on development of new pre and postoperative therapies. Oncogene p16 is implicated in pathogenesis of many human tumors and even in regulation of normal cellular growth, together with cycline, tyrosine kinasis and tumoral transforming and growth factors, like TGF-alpha and -beta and platelet derived growth factors (PDGF) ligands and receptors (alpha and beta). Loss of p16 has been exhaustively studied.PDGFR has been found activated and mutated on gastric stromal tumors where c-KIT, the most commonly marker found, is in wild type. PDGF receptors act over stromal origin cells and are not expressed in epithelial cells under normal physiologic conditions. PDGF-beta and its receptor have not been studied concerning expression and response to cellular growth inhibitors on non-stromal gastric tumors. The aim of this study has been detect immunohistochemistry expression of p16 and PDGFR-beta on gastric adenocarcinoma. Thirty six patients submitted to surgery for gastric adenocarcinoma among 1998-2002 years at Santa Casa de Porto Alegre Hospital have been studied. Variables investigated were: age, gender, tumor size and localization,number of ressected and metastatic nodes, histological type, surgical resection extension and pathological staging. No expression of PDGFR-beta has been detected on surgical specimens. Concerning to p16, loss of expression lower than 10% and 1% has been detected respectively on 89% and 79% of the specimens studied. There has been no correlation among p16 loss and the variables studied.

Physiological inflammation occurs in the female reproductive tract, but pathological inflammation is implicated in reproductive pathologies such as preterm labour and endometrial cancer. Preterm labour (PTL, before 37 weeks of gestation) is the leading cause of preterm birth, neonatal mortality and perinatal morbidities. Endometrial cancer is the commonest gynaecological cancer, and its pathogenesis is characterised by chronic inflammation. The overall aims of this thesis were (i) to develop an in vitro model of myometrial-monocyte interactions to replicate the events occurring in the myometrium in preterm labour (ii) to determine the effects of potential therapeutics such as lipoxins, IL-10 and progesterone, on inflammation, and (iii) to characterise the lipoxin pathway in endometrial adenocarcinoma. Macrophages infiltrate the pregnant myometrium during labour; however the role of these cells is unclear. A myometrial-monocyte coculture model was developed either using non-pregnant primary myometrial smooth muscle cells (UtSMCs), or immortalised pregnant human myometrial cells (PHM1-41), with primary monocytes from term (38-41 weeks of gestation), non-labouring pregnant women. Cultures were stimulated with the toll-like receptor 4 agonist lipopolysaccharide (LPS), in the presence or absence of each of lipoxins, IL-10 and progesterone. A significant and synergistic increase in IL-6 and IL-8 secretion was found in the UtSMC/monocyte coculture after stimulation with LPS for 24 hours, compared to LPS-treated UtSMCs, or monocytes alone, but the increase in IL-6 and IL-8 secretion was not inhibited by lipoxin, epi-lipoxin or benzo-lipoxin. The PHM1-41/monocyte coculture both alone and in response to LPS treatment generated significantly increased IL-6 and IL-8 secretion, compared to vehicle treatment in the coculture and compared to the culture of either cell type alone. IL-1β and TNFα secretion were only detected from the PHM1/monocyte coculture, and monocytes alone. Use of a TNFα blocking antibody partially suppressed LPS-induced IL-6 and IL-8 secretion in the coculture. Coculture of PHM1/monocytes resulted in increased secretion of multiple mediators including pro-inflammatory cytokines, chemokines and growth factors compared to culture of either PHM1 cells or primary monocytes separately, both with vehicle and with LPS. IL-10 inhibited LPS-induced IL-6 and IL-8 secretion from the coculture, as did progesterone, which also inhibited GM-CSF, MCP-1 and CXCL5 secretion. Myocyte contraction, measured by PHM1-41 cells embedded in collagen was increased by primary monocyte treatment. This suggests that not only do infiltrating monocytes increase myometrial inflammation but they can induce myometrial smooth muscle contraction. In endometrial adenocarcinoma, the lipoxin synthesis enzymes, ALOX-5 and -15 and FPR2 mRNA expression were upregulated compared to proliferative phase endometrium, with FPR2, a reported lipoxin receptor, immunolocalised in endometrial adenocarcinoma tissue. Additionally, TNFα treatment of Ishikawa endometrial adenocarcinoma cells increased FPR2 mRNA expression, and upregulation of FPR2 mRNA also occurred in xenograft tumours from CD1 nude mice, compared to the Ishikawa cells from which they originated. These findings highlight FPR2 expression in endometrial adenocarcinoma, and suggest this receptor could mediate inflammatory signals, and lipoxins could be produced by ALOX-5 and ALOX-15. Collectively, these data describe the novel effects of monocytes in the regulation of myometrial smooth muscle cell inflammation, and demonstrate a mechanism by which myometrial inflammation during both term and preterm labour is triggered by infiltrating macrophages. This myocyte/monocyte inflammation is regulated in part by TNFα, and can be suppressed by both IL-10 and progesterone co-treatment. Components of the lipoxin pathway are present in endometrial adenocarcinoma, but their role in regulation of inflammation is still to be elucidated. Future research to clarify the processes, by which leukocyte recruitment is regulated at labour and the role of monocyte/macrophages in altering myocyte properties, could help to elucidate the mechanisms coupling inflammation to labour and provide more appropriate targets for the treatment of PTL.