Involvement of Cox-2 in the metastatic potential of chemotherapy-resistant breast cancer cells

<p>Abstract</p> <p>Background</p> <p>A major problem with the use of current chemotherapy regimens for several cancers, including breast cancer, is development of intrinsic or acquired drug resistance, which results in disease recurrence and metastasis. However, the mechanisms underlying this drug resistance are unknown. To study the molecular mechanisms underlying the invasive and metastatic activities of drug-resistant cancer cells, we generated a doxorubicin-resistant MCF-7 breast cancer cell line (MCF-7/DOX).</p> <p>Methods</p> <p>We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, DNA fragmentation assays, Western blot analysis, cell invasion assays, small interfering RNA (siRNA) transfection, reverse transcription-polymerase chain reaction, experimental lung metastasis models, and gelatin and fibrinogen/plasminogen zymography to study the molecular mechanism of metastatic activities in MCF-7/DOX cells.</p> <p>Results</p> <p>We found that MCF-7/DOX acquired invasive activities. In addition, Western blot analysis showed increased expression of epidermal growth factor receptor (EGFR) and Cox-2 in MCF-7/DOX cells. Inhibition of Cox-2, phosphoinositide 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase (MAPK) pathways effectively inhibited the invasive activities of MCF-7/DOX cells. Gelatin and fibrinogen/plasminogen zymography analysis showed that the enzymatic activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator were markedly higher in MCF-7/DOX cells than in the MCF-7 cells. <it>In vitro </it>invasion assays and mouse models of lung metastasis demonstrated that MCF-7/DOX cells acquired invasive abilities. Using siRNAs and agonists specific for prostaglandin E (EP) receptors, we found that EP1 and EP3 played important roles in the invasiveness of MCF-7/DOX cells.</p> <p>Conclusions</p> <p>We found that the invasive activity of MCF-7/DOX cells is mediated by Cox-2, which is induced by the EGFR-activated PI3K/Akt and MAPK pathways. In addition, EP1 and EP3 are important in the Cox-2-induced invasion of MCF-7/DOX cells. Therefore, not only Cox-2 but also EP1 and EP3 could be important targets for chemosensitization and inhibition of metastasis in breast cancers that are resistant to chemotherapy.</p

Acidente por serpentes do gênero Bothrops: série de 3.139 casos

Em avaliação dos prontuários médicos de 3.139 pacientes picados por serpentes do gênero Bothrops atendidos no Hospital Vital Brazil (HVB), de 1981 a 1990, observou-se maior acometimento do sexo masculino (75,7%). Em 1.412 casos (45,0%) a serpente foi identificada, sendo 1.376 B. jararaca, 20 B. jararacussu, 11 B. neuwiedi, 2 B. moojeni, 2 B. alternatus e 1 B. pradoi. As regiões anatômicas mais comumente picadas foram: pé (47,5%) e mão (21,3%). O torniquete foi realizado em 38,2% dos casos e sua freqüência diminuiu durante esse período (p < 0,001). As manifestações clínicas mais freqüentes foram: dor (95,6%), edema (95,4%), equimose (56,1%), bolha (13,8%), necrose (16,5%), abscesso (11,0%), sangramento extratecidual (12,3%), insuficiência renal (1,6%) e choque (0,7%). A coagulação sanguínea foi avaliada em 2.990 casos e estava alterada em 1.730 (57,9%). Ocorreram 21 amputações (0,7%) e 9 óbitos (0,3%). A dose de soro administrada no HVB diminuiu ao longo desse período (p < 0,001).<br>Medical records of 3,139 patients bitten by Bothrops snakes and attended at Vital Brazil Hospital (HVB) from 1981 to 1990 were reviwed. They were more frequent in males (75.7%). In 1,412 cases (45.0%) the snake was classified by species, and 1,376 were B. jararaca, 20 B. jararacussu, 11 B. neuwiedi, 2 B. moojeni, 2 B. alternatus e 1 B. pradoi. The most frequent bitten anatomic regions were: foot (47.5%) and hand (21.3%). Tourniquet was used in 38.2% of the cases and its frequency fell down during the study period (p < 0.05). The clinical features at the bite site were: pain (95.6%), swelling (95.4%), echimosis (56.1%), blisters (13.8%), necrosis (16.5%), and abscess (11.0%). Systemic manifestations were: bleeding (12.3%), acute renal failure (1.6%), and shock (0.7%). There were blood coagulation disorders in 1,730 (57.9%) of the 2,990 cases. There were 21 amputations (0.7%) and 9 deaths (0.3%). The average serum dose that was used in treatment fell down during the study period (p < 0.001)

Perfil epidemiológico da raiva na região Noroeste do Estado de São Paulo no período de 1993 a 2007 Epidemiological profile of rabies in the northwestern region of São Paulo State, from 1993 to 2007

Descreve-se a epidemiologia da raiva animal na região de Araçatuba, noroeste do estado de São Paulo, durante o período de 1993 a 2007, com base nos resultados dos diagnósticos realizados em laboratórios da região, utilizando as técnicas de imunofluorescência direta e inoculação intracerebral em camundongos. De 10.579 amostras analisadas, 4,9% foram positivas (518/10.579). Os casos em cães corresponderam a 67% (346/518) do total e ocorreram entre 1993 a 1997. Dentre as demais amostras positivas, 16% do total (84/518) foi detectado em bovinos e 9,7% (50/518) em morcegos. Dos 42 municípios da região, 23 (55%) apresentaram pelo menos um caso positivo da doença, sendo que 13 deles registraram casos em morcegos. Foram identificados três ciclos distintos da raiva na região Noroeste do Estado de São Paulo, o ciclo urbano caracterizado predominantemente pela raiva canina (1993 a 1997) e os ciclos aéreo e rural, a partir de 1998 com predominância de casos em quirópteros nas áreas urbanas e em herbívoros.<br>The epidemiology of animal rabies in the region of Araçatuba, in the northwest of São Paulo State, from 1993 to 2007, is described according to the results from diagnoses made at laboratories in the region, using the fluorescent antibody and mouse inoculation tests. Out of 10,579 samples analyzed, 4.9% were positive (518/10,579). Dogs accounted for 67% of the cases (346/518) and these occurred between 1993 and 1997. Among the other positive samples, 16% (84/518) were in cattle and 9.7% (50/518) were in bats. Among the 42 municipalities in the region, 23 (55%) presented at least one rabies-positive case, while 13 of them had cases in bats. Three distinct cycles of rabies were identified in the northwestern region of the State of São Paulo: the urban cycle characterized predominantly by canine rabies (1993 to 1997); and the aerial and rural cycles starting in 1998, with predominance of cases in bats in urban areas and in herbivores