It has been estimated that LAGB represents about 42% of bariatric operations performed worldwide. There are a number of different adjustable gastric bands available. Few attempts have been made to compare the influence of band design differences for efficiency and complication rate. There are no accepted criteria for choosing this particular operation. In the dissertation we compared one year results after adjustable gastric banding using different adjustable gastric bands – SAGB and MiniMizer Extra. We have determined that laparoscopic adjustable gastric banding is effective and safe bariatric procedure: the average percentage of initial excess body mass index loss was 33,1 ± 21,9%; 34.1% of patients achieved fair, 30,6% - good, 9,4% - very good and 2,4% - excellent results according to BAROS; only 5 (4,9%) major complications were diagnosed. No radical differences were stated between the efficiency and complication rate of the compared adjustable gastric bands: the average percentage of initial excess body mass index loss in SAGB and MiniMizer Extra groups was 28,9 ± 21,3% and 36,8 ± 22.1% respectively, p=0.075; major complication rate was 0 (0%) and 5 (9.3%) respectively, p=0.069. Patients at the age of 40 and older achieved better results using MiniMizer Extra band - the average percentage of initial excess body mass index loss was 37,5 ± 20,8% versus 23,6 ± 13,8% in SAGB group, p=0.002. Patients with initial BMI ≤ 47 achieved better results using MiniMizer Extra band... [to full text] / Šiuo metu Pasaulyje skrandžio apjuosimo reguliuojama juosta operacijos sudaro apie 43 % visų chirurginių operacijų, atliekamų nutukimui gydyti. Iki šiol nėra pilnai ištirta operacijoje naudojamų skrandį apjuosiančių reguliuojamų juostų konstrukcijos skirtumų įtaka gydymo rezultatams, taip pat nėra priimtų pacientų atrankos šiai operacijai kriterijų. Disertacijoje palyginome vienerių metų nutukimo chirurginio gydymo rezultatus naudojant skirtingas skrandį apjuosiančias reguliuojamas juostas – SAGB ir MiniMizer Extra. Nustatėme, kad skrandžio apjuosimo reguliuojama juosta operacija yra efektyvus ir saugus nutukimo gydymo būdas: vidutinis procentinis perteklinio kūno masės indekso sumažėjimas buvo 33,1 ± 21,9%; vertinant pagal BAROS, 34.1% pacientų pasiekė patenkinamą, 30,6% - gerą, 9,4% – labai gerą ir 2,4% – puikų gydymo rezultatą; pasitaikė 5 (4,9%) „didžiosios” komplikacijos. Esminių skirtumų tarp lygintų juostų efektyvumo ir komplikacijų skaičiaus po vienerių metų po operacijos nenustatyta: vidutinis procentinis perteklinio kūno masės indekso sumažėjimas SAGB ir MiniMizer Extra grupėse buvo atitinkamai 28,9 ± 21,3% ir 36,8 ± 22.1%, p=0.075, o „didžiųjų” komplikacijų skaičius atitinkamai 0 (0%) ir 5 (9.3%), p=0.069. 40 metų ir vyresni pacientai geresnių rezultatų pasiekė naudojant MiniMizer Extra juostą - vidutinis procentinis perteklinio kūno masės indekso sumažėjimas buvo 37,5 ± 20,8% prieš 23,6 ± 13,8 % SAGB grupėje, p=0.002. Pacientai, kurių pradinis KMI ≤ 47, geresnių... [toliau žr. visą tekstą]

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Inadequate delivery of nutrition to the critically ill is common, and may adversely affect clinical outcomes, including survival. This thesis reports studies designed to characterise the gastrointestinal dysfunction underlying feed intolerance in the critically ill, as well as the pathophysiology of these dysfunctions, and investigate potential therapeutic measures. While it has been established that enteral nutrition is frequently unsuccessful in the critically ill, assessment of the success of feeding in an Australian intensive care unit (ICU) had not been performed previously. A prospective survey examined the incidence of, and risk factors for, feed intolerance in the ICU at the Royal Adelaide Hospital and demonstrated that, in 40 patients receiving enteral feeding, only about 60% of their nutritional requirements were met at the end of the first week. The main cause for this lack of success was large gastric residual volumes, indicative of delayed gastric emptying (GE). This study, accordingly, quantified the limitations of nutritional delivery in contemporary practice in a local ICU. The results suggest that a better understanding of the pathogenesis underlying this problem is warranted in order to direct research into improved therapies. Scintigraphy is the most accurate technique to measure GE, but is difficult to perform in the ICU. A simpler, more convenient, test would increase the accessibility of GE measurement for both research and clinical purposes. A study comparing a breath test technique and gastric residual volume measurement to the scintigraphic measurement of GE in 25 mechanically ventilated patients demonstrated that GE measured by a breath test technique closely correlated with that measured by scintigraphy. While the breath test had a specificity of 100% it only had a sensitivity of about 60% in the prediction of delayed GE. Similarly, gastric residual volume measurement correlated with scintigraphic measurement of GE but also lacked sensitivity. The breath test has previously been demonstrated to be highly reproducible and it represents a useful option for repeated measurement of GE in the same patient. It is therefore likely to be useful to determine changes in GE over time or in response to a therapeutic intervention. There is a lack of information about the prevalence and determinants of delayed GE in the critically ill. Previous studies have substantial limitations and scintigraphic measurement of GE has only rarely been used. A study comparing GE measured by scintigraphy in 25 patients to 14 healthy subjects demonstrated that GE was delayed in approximately 50% of the ICU patients (>10% retention at 4h) and markedly delayed in about 20% (>50% retention at 4h). Patients with trauma and sepsis appeared to have a relatively higher prevalence of delayed GE (80% and 75% respectively). In addition, the longer the patient had been in ICU the more normal the rate of GE. Quantification of delayed GE may prove useful by defining patients who may benefit from preventative or therapeutic options. The abnormalities in gastrointestinal motility underlying delayed GE in the critically ill are poorly characterised. Simultaneous manometric and gastric emptying measurements were performed in 15 mechanically ventilated patients and 10 healthy subjects. These studies demonstrated that delayed GE was associated with reduced antral activity, increased pyloric activity and increased retrograde duodenal activity in the patients. Persistent fasting motility during feeding was also frequently observed. Furthermore, the feedback response to small intestinal nutrients was enhanced. This latter observation may provide an explanation for the delayed GE and warrants further investigation. Recent studies suggest that the hormone cholecystokinin may be a mediator of increased small intestinal feedback and, if confirmed, this has clear therapeutic implications. Nutrient absorption has rarely been measured in the critically ill. GE and glucose absorption (using 3-O-methyl glucose) were measured simultaneously in 19 ICU patients and compared to 19 healthy subjects. Glucose absorption was shown to be markedly reduced in the patients. Slow GE was associated with delayed, and reduced, absorption. However, glucose absorption was also reduced in patients with normal GE suggesting that reduced glucose absorption in critical illness is only partly due to delayed GE. Accordingly, measures to improve the effectiveness of GE and thereby improve overall nutritional status may be compromised by abnormal small intestinal absorption. The mechanisms underlying this warrant further investigation. A number of therapeutic options directed at improving the delivery of nutrition were examined. In a study involving 20 mechanically ventilated patients, administration of 200mg erythromycin intravenously was shown to be superior to placebo for treating feed intolerance. The optimal dose of erythromycin, however, was unclear. In a subsequent study involving 35 ICU patients, GE was measured using a breath test technique, before and after 2 different doses of erythromycin or placebo and a ‘low’ intravenous dose (70mg) of erythromycin appeared to be as effective as a ‘moderate’ dose (200mg). Both doses were only effective in subjects who had delayed GE at baseline. Based on the outcome of these studies, low doses of erythromycin have subsequently been routinely used to treat feed intolerance in the critically ill patients at the Royal Adelaide Hospital. Animal and human studies suggested that the antibiotic, cefazolin, may have a prokinetic effect. Cefazolin, however, did not demonstrate similar prokinetic activity at a ‘low’ dose (50mg) in a critically ill cohort. The results of this study do not support the use of this agent, at this dose, as a prokinetic, in this population. If nasogastric administration of nutrition proves unsuccessful an alternative is to infuse nutrient directly into the small intestine. However, the placement of feeding tubes distal to the pylorus is technically difficult. A novel technique for postpyloric tube insertion was examined with promising results. In summary, the studies described in this thesis have provided a number of insights relevant to the management of the critically ill by quantifying the prevalence of feed intolerance and delayed GE, characterising some of the disturbances in gastrointestinal motility underlying this problem, and evaluating a number of therapeutic interventions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345143 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Inadequate delivery of nutrition to the critically ill is common, and may adversely affect clinical outcomes, including survival. This thesis reports studies designed to characterise the gastrointestinal dysfunction underlying feed intolerance in the critically ill, as well as the pathophysiology of these dysfunctions, and investigate potential therapeutic measures. While it has been established that enteral nutrition is frequently unsuccessful in the critically ill, assessment of the success of feeding in an Australian intensive care unit (ICU) had not been performed previously. A prospective survey examined the incidence of, and risk factors for, feed intolerance in the ICU at the Royal Adelaide Hospital and demonstrated that, in 40 patients receiving enteral feeding, only about 60% of their nutritional requirements were met at the end of the first week. The main cause for this lack of success was large gastric residual volumes, indicative of delayed gastric emptying (GE). This study, accordingly, quantified the limitations of nutritional delivery in contemporary practice in a local ICU. The results suggest that a better understanding of the pathogenesis underlying this problem is warranted in order to direct research into improved therapies. Scintigraphy is the most accurate technique to measure GE, but is difficult to perform in the ICU. A simpler, more convenient, test would increase the accessibility of GE measurement for both research and clinical purposes. A study comparing a breath test technique and gastric residual volume measurement to the scintigraphic measurement of GE in 25 mechanically ventilated patients demonstrated that GE measured by a breath test technique closely correlated with that measured by scintigraphy. While the breath test had a specificity of 100% it only had a sensitivity of about 60% in the prediction of delayed GE. Similarly, gastric residual volume measurement correlated with scintigraphic measurement of GE but also lacked sensitivity. The breath test has previously been demonstrated to be highly reproducible and it represents a useful option for repeated measurement of GE in the same patient. It is therefore likely to be useful to determine changes in GE over time or in response to a therapeutic intervention. There is a lack of information about the prevalence and determinants of delayed GE in the critically ill. Previous studies have substantial limitations and scintigraphic measurement of GE has only rarely been used. A study comparing GE measured by scintigraphy in 25 patients to 14 healthy subjects demonstrated that GE was delayed in approximately 50% of the ICU patients (>10% retention at 4h) and markedly delayed in about 20% (>50% retention at 4h). Patients with trauma and sepsis appeared to have a relatively higher prevalence of delayed GE (80% and 75% respectively). In addition, the longer the patient had been in ICU the more normal the rate of GE. Quantification of delayed GE may prove useful by defining patients who may benefit from preventative or therapeutic options. The abnormalities in gastrointestinal motility underlying delayed GE in the critically ill are poorly characterised. Simultaneous manometric and gastric emptying measurements were performed in 15 mechanically ventilated patients and 10 healthy subjects. These studies demonstrated that delayed GE was associated with reduced antral activity, increased pyloric activity and increased retrograde duodenal activity in the patients. Persistent fasting motility during feeding was also frequently observed. Furthermore, the feedback response to small intestinal nutrients was enhanced. This latter observation may provide an explanation for the delayed GE and warrants further investigation. Recent studies suggest that the hormone cholecystokinin may be a mediator of increased small intestinal feedback and, if confirmed, this has clear therapeutic implications. Nutrient absorption has rarely been measured in the critically ill. GE and glucose absorption (using 3-O-methyl glucose) were measured simultaneously in 19 ICU patients and compared to 19 healthy subjects. Glucose absorption was shown to be markedly reduced in the patients. Slow GE was associated with delayed, and reduced, absorption. However, glucose absorption was also reduced in patients with normal GE suggesting that reduced glucose absorption in critical illness is only partly due to delayed GE. Accordingly, measures to improve the effectiveness of GE and thereby improve overall nutritional status may be compromised by abnormal small intestinal absorption. The mechanisms underlying this warrant further investigation. A number of therapeutic options directed at improving the delivery of nutrition were examined. In a study involving 20 mechanically ventilated patients, administration of 200mg erythromycin intravenously was shown to be superior to placebo for treating feed intolerance. The optimal dose of erythromycin, however, was unclear. In a subsequent study involving 35 ICU patients, GE was measured using a breath test technique, before and after 2 different doses of erythromycin or placebo and a ‘low’ intravenous dose (70mg) of erythromycin appeared to be as effective as a ‘moderate’ dose (200mg). Both doses were only effective in subjects who had delayed GE at baseline. Based on the outcome of these studies, low doses of erythromycin have subsequently been routinely used to treat feed intolerance in the critically ill patients at the Royal Adelaide Hospital. Animal and human studies suggested that the antibiotic, cefazolin, may have a prokinetic effect. Cefazolin, however, did not demonstrate similar prokinetic activity at a ‘low’ dose (50mg) in a critically ill cohort. The results of this study do not support the use of this agent, at this dose, as a prokinetic, in this population. If nasogastric administration of nutrition proves unsuccessful an alternative is to infuse nutrient directly into the small intestine. However, the placement of feeding tubes distal to the pylorus is technically difficult. A novel technique for postpyloric tube insertion was examined with promising results. In summary, the studies described in this thesis have provided a number of insights relevant to the management of the critically ill by quantifying the prevalence of feed intolerance and delayed GE, characterising some of the disturbances in gastrointestinal motility underlying this problem, and evaluating a number of therapeutic interventions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345143 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Προσχεδιασμένη συγκριτική διπλή τυφλή μελέτη της αποτελεσματικότητας της επιμήκους γαστρεκτομής (LSG) και της μερικής γαστρικής παράκαμψης Roux-en-Y (LRYGB) σε ασθενείς με κλινικά σοβαρή παχυσαρκία (BMI 35-49,9) Η λαπαροσκοπική γαστρική παράκαμψη (LRYGB) αποτελεί στις μέρες μας το χρυσό κανόνα για τη χειρουργική αντιμετώπιση της κλινικά σοβαρής παχυσαρκίας. Η λαπαροσκοπική επιμήκης γαστρεκτομή (LSG) είναι μία σχετικώς νέα επέμβαση περιοριστικού τύπου η οποία τελευταία έχει αρχίσει να εφαρμόζεται ως μοναδική επέμβαση για την κλινικά σοβαρή παχυσαρκία. Η παρούσα προοπτική διπλή τυφλή μελέτη έχει σκοπό να διερευνήσει την ασφάλεια των παραπάνω επεμβάσεων καθώς και την αποτελεσματικότητα τους σε χρονικό ορίζοντα τριών χρόνων. Μέθοδος: Εξήντα ασθενείς με δείκτη σωματικής μάζας <50 Kg/m2 μετά από τυχαιοποίηση υπεβλήθησαν τριάντα σε LSG και τριάντα σε LRYGB. Οι ασθενείς παρακολουθήθηκαν μετεγχειρητικά για τρία χρόνια. Στο διάστημα αυτό καταγράφηκε η απώλεια βάρους, η πρώιμη και όψιμη νοσηρότητα και θνητότητα, η ίαση των συνοδών της παχυσαρκίας νόσων και η ανάπτυξη μικροθρεπτικών ανεπαρκειών μετά τους δύο τύπους χειρουργείων. Αποτελέσματα: Η θνητότητα ήταν μηδενική και στους δύο τύπους επεμβάσεων. Δεν καταγράφηκε σημαντική διαφορά στην πρώιμη (10% μετά από LRYGBP και 13.3% μετά από LSG, P>0.05) και όψιμη νοσηρότητα (10% σε κάθε ομάδα) μετά και τους δύο τύπους χειρουργείων. Η απώλεια βάρους ήταν στατιστικώς μεγαλύτερη μετά από LSG καθόλη τη διάρκεια της μελέτης. Τον τρίτο μετεγχειρητικό χρόνο η επί τις εκατό απώλεια του υπερβάλλοντος βάρους κυμαίνονταν στο 62.09% μετά από LRYGBP και στο 68.46% μετά από LSG (p=0.02). Δεν παρατηρήθηκε σημαντική διαφορά ως προς την ίαση των συνοδών της παχυσαρκίας νόσων, εκτός από τη δυσλιπιδαιμία η οποία βελτιώθηκε σε σημαντικότερο βαθμό μετά από LRYGB και την υπέρταση η οποία βελτιώθηκε σε σημαντικότερο βαθμό μετά από LSG. Ανεπάρκεια μικροθρεπτικών συστατικών παρατηρήθηκε σε ανάλογο βαθμό μετά τις δύο επεμβάσεις εκτός από την έλλειψη βιταμίνης Β12 η οποία παρατηρήθηκε σε μεγαλύτερο βαθμό μετά από LRYGB (P<0.001). Συμπεράσματα: Και οι δύο επεμβάσεις είναι ασφαλείς και αποτελεσματικές ως προς την απώλεια βάρους και την ίαση των συνοδών της παχυσαρκίας νόσων. Η LSG συνοδεύεται από λιγότερες μεταβολικές ανεπάρκειες και δεν απαιτεί τη χορήγηση συμπληρωμάτων εφ’ όρου ζωής. Η LSG φαίνεται ότι είναι μία υποσχόμενη επέμβαση για την κλινικά σοβαρή παχυσαρκία η οποία στα τρία χρόνια μετεγχειρητικής παρακολούθησης επιτυγχάνει μεγαλύτερη απώλεια βάρους από την LRYGB. / The efficacy of sleeve gastrectomy (LSG) and Roux en Y gastric bypass (LRYGB) in patients with morbid obesity (BMI 35-49,9). A comparative double-blind randomized trial Background: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is currently the gold standard bariatric procedure for the treatment of morbid obesity. Laparoscopic sleeve gastrectomy (LSG) is an innovative restrictive procedure which has been increasingly applied as a sole bariatric procedure. A randomized trial was conducted to evaluate perioperative safety (30-day) and 3-years results. Methods: Sixty patients with body mass index (BMI) ≤ 50 Kg/m2 were randomized to LRYGB or LSG. Patients were monitored for 3 years after operation and throughout the study period weight loss, early and late complications, improvement of obesity related comorbidities and nutritional deficiencies were compared between studied groups. Results: There was no death in either group and no significant difference in early (10% after LRYGBP and 13.3% after LSG, P>0.05) and late morbidity (10% in each group). Weight loss was significantly better after LSG throughout the study period. At 3 years %EWL reached 62.09% after LRYGBP and 68.46% after LSG (p=0.02). There was no significant difference in the overall improvement of comorbidities but dyslipidemia improved more after LRYGB, whereas hypertension resolved more after LSG. Nutritional deficiencies occurred at same rate in the two groups except to vitamin B12 deficiency which was more common after LRYGB (P<0.001). Conclusion: In conclusion, LSG and LRYGBP are equally safe and effective in the amelioration of comorbidities, while LSG is associated with fewer postoperative metabolic deficiencies, without the need of supplementation. Furthermore, LSG is a promising bariatric procedure, since it seems to be superior to LRYGB at 3 years follow up on weight reduction.

Orientador: Maria Rita Marques de Oliveira / Resumo: A obesidade é resultante de uma complexa interação entre fatores genéticos, ambientais e metabólicos, cujo controle dos casos extremos tem se realizado com cirurgia. Embora efetivos, os resultados da cirurgia são variáveis e pouco se sabe sobre os efeitos em longo prazo. Objetivo: avaliar o efeito tardio da cirurgia bariátrica considerando técnica cirúrgica, consumo alimentar e as variações de peso, diante de um desfecho clínico desejável e indesejável. Métodos: Este estudo prospectivo não concorrente envolveu a participação de 74 mulheres (idade 42,2 ± 6,2 anos; IMC 44,7 ± 6,5 kg/m2) submetidas à cirurgia de derivação gástrica em Y-Roux (DGYR). Os pacientes foram categorizados em dois grupos de acordo com a variação de peso pós-cirúrgica: Grupo 1 – variação ≤10% do menor peso alcançado (desfecho desejável); Grupo 2 – reganho de peso >10% do menor peso alcançado (não desejável). Foram avaliados peso corporal, % perda do excesso de peso (%PEP), peso mínimo atingido, presença de comorbidades, consumo de energia e macronutrientes e Baros. Resultados: Após 6 anos da cirurgia, 35/74 pacientes apresentaram reganho de peso >10% do menor peso atingido (Grupo 2). Os grupos eram homogêneos para variáveis pré-cirúrgicas. A mediana do menor peso atingido para os pacientes do Grupo 1 foi de 74 (67,8 - 80) kg e 71,4 (64,6 – 80,8) Kg para os pacientes do Grupo 2, alcançados em 24 (18 – 42) e 18 (12 – 24) meses, respectivamente (p=0,017). O %PEP dos pacientes do Grupo 1 foi de 77% e 66% para... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Le T-DM1 est un immunoconjugué composé de l'anticorps trastuzumab qui cible HER2 lié au DM1, un agent anti-tubuline dérivé de la maytansine. Malgré son efficacité, la résistance acquise au T-DM1 a été démontré lors des tests précliniques et chez certains patients. Nous avons développé des lignées résistantes à partir de la lignée de cancer du sein MDA-MB-361 et de la lignée de cancer de l'œsophage OE-19, que nous avons exposées au T-DM1 à doses croissantes pendant une longue durée en absence ou en présence de ciclosporine A (CsA). A partir de ces conditions nous avons obtenus les lignées “TR” qui ont été exposées uniquement au T-DM1 et “TCR” qui ont été exposées au T-DM1 et CsA. Nous avons observé une augmentation de la vitesse de migration et une diminution de la force d'adhésion chez OE-19 TCR associées à une sensibilité accrue à un inhibiteur de RHOA. Aussi, la voie des prostaglandines était dérégulée chez OE-19 TR et TCR, avec une forte augmentation de l'expression de COX-2 et de prostaglandine E2 dans la lignée OE-19 TR. La sensibilité à l'aspirine, un inhibiteur des cyclooxygenases 1-2, était accrue chez les deux lignées OE-19 résistantes par rapport à la lignée parentale. En conclusion nous avons démontré que différentes voies de signalisation peuvent être impliquées dans la résistance au T-DM1. Nos résultats restent à être validés chez les patients. Nous suggérons que cibler la voie de régulation de la composition du cytosquelette ou la voie des prostaglandines pourrait permettre d'obtenir un effet thérapeutique dans le cas de cancers résistants au T-DM1 / T-DM1 is an antibody-drug conjugate composed of the monoclonal antibody trastuzumab linked to DM1, a potent tubulin binding agent. Despite its efficacy in the treatment of HER2-positive breast cancer patients, acquired resistance to T-DM1 was observed during clinical trials. In order to study resistance mechanisms to T-DM1, we developed resistance models using OE-19 (esophageal) and MDA-MB-361 (breast) cancer cell lines in the absence or presence of ciclosporin A (CsA), an inhibitor of MDR1 mediated efflux. Resistant cells selected with T-DM1 alone are named “TR” and cells selected in the presence of T-DM1 and CsA are called “TCR”. OE-19 TCR cells showed modifications in adhesion gene expression, migration and adhesion strength, combined with an increased sensitivity to a RHOA inhibitor. Also, OE-19 TR cells presented an overexpression of COX-2 associated with an increased amount of PGE2 in the supernatant. A deregulation of the genes involved in the prostaglandin pathways was found in OE-19 TR and TCR cells, associated with increased sensitivity to aspirin. In conclusion, we found two signaling pathways deregulated in cell lines resistant to T-DM1. These results need to be validated using samples from patients resistant to T-DM1. Targeting the adhesion or the prostaglandin pathway could be of benefit for patients with T-DM1 resistant cancers

Made available in DSpace on 2014-06-11T19:26:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-28Bitstream added on 2014-06-13T18:29:22Z : No. of bitstreams: 1 silva_hm_me_sjrp.pdf: 508031 bytes, checksum: 56b635113c96c5bc5c2ffa3a4cb5324a (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer gástrico é a segunda causa de morte por câncer no mundo e o quinto tipo com maior prevalência no Brasil, sendo previstos 21.800 casos novos em 2008. Esta neoplasia apresenta etiologia bastante complexa, envolvendo fatores genéticos e ambientais. Os fatores etiológicos de maiores destaques incluem a infecção pela bactéria Helicobacter pylori, a ingestão de determinados alimentos, como defumados, enlatados e com elevada quantidade de sal, além do estilo de vida dos indivíduos, associado ao consumo de cigarro e álcool. Uma lesão pré-cancerosa importante no desenvolvimento da neoplasia gástrica é a metaplasia intestinal, podendo aumentar o seu risco em até 10 vezes. Atualmente é reconhecida a participação de alterações epigenéticas como metilação aberrante do DNA, que atua de forma igualmente relevante e complementar no processo de desenvolvimento e progressão do câncer. Vários genes com papel importante no controle do ciclo celular, reparo do DNA, apoptose, angiogênese e adesão celular podem apresentar expressão alterada devido metilação aberrante de sua região promotora, assim a investigação do padrão de metilação de genes envolvidos com o processo neoplásico pode ser uma estratégia interessante para a indicação de marcadores moleculares que possam auxiliar no diagnóstico precoce do câncer. Desta forma, no presente trabalho foi investigado o padrão de metilação dos genes WT1 e RARß em metaplasia intestinal (35 amostras) e suas respectivas mucosas gástricas normais, em comparação com o câncer gástrico (8 amostras) também com suas respectivas mucosas normais, através da técnica MS-PCR (Methylation Specific PCR). Devido à participação da infecção pela H. pylori na carcinogênese gástrica, foi investigada molecularmente a presença dessa bactéria nas amostras... / Worldwide, the gastric cancer is the second cause of death by cancer. In Brazil, it is the fifth type with more abundant, foreseen 21.800 new cases in 2008. This neoplasia presents very complex etiology involving genetic and environmental factors. The main etiologic factors include: infection by H. pylori, intake of specific foods such as curing food, canned food, and high consumption of salt wealthy food, besides people life style associated to alcohol and cigarette consumptions. An important previous-cankered lesion in development of gastric neoplasia is the intestinal metaplasia, what can increase your risk in ten times. At this moment, it is recognized the participation of epigenetic alterations like ADN aberrant methylation, which actuate in a same way considerable and complementary in development process and cancer evolution. Many genes with important role in control of cellular cycle, ADN repair, apoptosis, angiogenesis and cellular adhesion can present changed expression due aberrant metthylation of your promoter region. In this manner, the investigation of metithyation pattern of genes involved with the neoplasic process can be an interesting strategy for the indication of molecular markers that can help in cancer precocious diagnosis. Thus, in this present study were investigated the metthylation pattern of RARß and WT1genes (35 samples) and their respective normal mucous gastrics by technic MSPCR (Methylation Specific PCR). Due to participation of infection by H. pylori in gastric carcinogenesis, it was too molecular investigated the presence of this bacterium in the studied samples and the possible association with the metthylation pattern presented by both genes. The results showed high pattern of methylation in both valued lesions, that is, 97% and 100%, respectively of methylated samples in metaplasia group ...(Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:26:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-17Bitstream added on 2014-06-13T20:14:35Z : No. of bitstreams: 1 jorge_yc_me_sjrp.pdf: 4700733 bytes, checksum: 1fa001424eaf0ffba4a8cdeb55c5fce5 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / No presente estudo foram investigados os níveis de expressão gênica e protéica da anexina-1 (ANXA1/AnxA1) e galectina-1 (LGALS1/Gal-1) na carcinogênese do estômago e associações com infecção pela Helicobacter pylori e o genótipo de virulência bacteriano cagA+. A análise foi realizada em 40 biópsias de mucosa gástrica com gastrite crônica (CG), 20 de câncer gástrico (GA) e 10 de mucosa normal (C), pelas técnicas de qPCR para quantificar os níveis de RNAm; imuno-histoquímica para caracterizar a expressão protéica na mucosa gástrica, e PCR para diagnóstico molecular da H. pylori e cepa cagA+. O estudo mostrou resultados inéditos quanto à expressão desses genes em gastrite crônica, ainda sem descrições na literatura. Foi demonstrada expressão relativa elevada do mRNA de ANXA1 em 80% dos casos de GA (média de 4,38 + 4,77) e em 90% dos casos de CG (média de 4,26 + 2,03), sem diferença significante entre os grupos (p = 0,33). O gene LGALS1 apresentou expressão elevada em 60% dos casos GA (média de 2,44 + 3,26) e, expressão constitutiva na CG (média de 0,43 + 3,13), mostrando, portanto, diferença significante entre os grupos (p < 0,01). A imuno-histoquímica revelou que as proteínas AnxA1 e Gal-1 não são expressas na mucosa normal. Ao contrário, durante o processo inflamatório de CG, imunomarcação citoplasmática positiva para a AnxA1 foi observada na porção basal do epitélio e estroma e, para Gal-1 a expressão foi constatada na porção apical e borda estriada do epitélio além do estroma. No adenocarcinoma tipo intestinal foi observada expressão citoplasmática em toda extensão epitelial e estroma tanto para a AnxA1 quanto para a Gal-1. Por outro lado, no tipo difuso imunomarcação positiva também foi observada no núcleo e membrana plasmática... / In this study we investigated the levels of gene and protein expression of annexin-1 (ANXA1/Anxa1) and galectin-1 (LGALS1/Gal-1) in gastric carcinogenesis and associations with Helicobacter pylori infection and bacterial virulence genotype cagA+. The analysis was performed in 40 biopsies of gastric mucosa with chronic gastritis (CG), 20 with gastric cancer (GA) and 10 of normal mucosa (C), by the techniques of qPCR to quantify mRNA levels, immunohistochemistry to characterize the protein expression in gastric mucosa, and PCR for molecular diagnosis of H. pylori cagA+ strains. This is the first study regarding the expression of these genes in chronic gastritis. High ANXA1expression levels were demonstrated in 80% of GA cases (mean 4.38 + 4.77) and in 90% of GC cases (mean 4.26 + 2.03), with no significant difference between groups (p = 0.33). High LGALS1 gene expression was found in 60% of GA cases (average 2.44 + 3.26), and constitutive expression was found in CG (mean 0.43 + 3.13), showing therefore a significant difference between groups (p <0.01). Immunohistochemistry revealed that the proteins AnxA1 and Gal-1 are not expressed in normal mucosa. In contrast, during the inflammatory process of CG, positive cytoplasmic immunostaining for AnxA1 was observed in the basal epithelium and stroma, and Gal-1 expression was detected in the apical portion and striated border of the epithelium and stroma. In intestinal-type adenocarcinoma was observed cytoplasmic expression in all epithelial and stromal extension for both AnxA1 and Gal-1. On the other hand, in diffuse-type adenocarcinoma positive immunostaining was also observed in the nucleus and plasma membrane of both proteins. Infection by H. pylori showed no association with the expression of both genes, but the genotype cagA+ is associated with about 2.5 times... (Complete abstract click electronic access below)