RESUMO
We report a case of primary gastric diffuse large B-cell lymphoma (DLBCL), de novo DLBCL without the features of mucosa-associated lymphoid tissue (MALT) lymphoma, which regressed after Helicobacter pylori (HP) eradication. A 27-year-old Japanese female with epigastralgia was revealed to have ulcerated lesions in the angle and antral regions on gastroscopy. Biopsy specimen was consistent with a diagnosis of DLBCL without MALT lymphoma component, indicating de novo development. Her clinical staging on the Lugano system was Stage I. HP was positive on a rapid urease test, and she received HP eradication therapy twice, because the first therapy was not successful. On gastroscopy performed 1 month after the second HP eradication therapy, no ulcerated lesion was noted, and the lymphoma cells had regressed histopathologically. (Acta gastro-enterol. belg., 2016, 79, 367-369A).
Assuntos
Amoxicilina/administração & dosagem , Claritromicina/administração & dosagem , Infecções por Helicobacter , Helicobacter pylori , Lansoprazol/administração & dosagem , Linfoma Difuso de Grandes Células B , Metronidazol/administração & dosagem , Neoplasias Gástricas , Adulto , Antibacterianos/administração & dosagem , Monitoramento de Medicamentos/métodos , Feminino , Gastroscopia/métodos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/isolamento & purificação , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Estadiamento de Neoplasias , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
Current surgical intervention of craniofacial defects caused by injuries or abnormalities uses reconstructive materials, such as autologous cartilage grafts. Transplantation of autologous tissues, however, places a significant invasiveness on patients, and many efforts have been made for establishing an alternative graft. Recently, we and others have shown the potential use of reconstructed elastic cartilage from ear-derived chondrocytes or progenitors with the unique elastic properties. Here, we examined the differentiation potential of canine joint cartilage-derived chondrocytes into elastic cartilage for expanding the cell sources, such as hyaline cartilage. Articular chondrocytes are isolated from canine joint, cultivated, and compared regarding characteristic differences with auricular chondrocytes, including proliferation rates, gene expression, extracellular matrix production, and cartilage reconstruction capability after transplantation. Canine articular chondrocytes proliferated less robustly than auricular chondrocytes, but there was no significant difference in the amount of sulfated glycosaminoglycan produced from redifferentiated chondrocytes. Furthermore, in vitro expanded and redifferentiated articular chondrocytes have been shown to reconstruct elastic cartilage on transplantation that has histologic characteristics distinct from hyaline cartilage. Taken together, cultured hyaline cartilage-derived chondrocytes are a possible cell source for elastic cartilage reconstruction.
Assuntos
Condrócitos/transplante , Condrogênese , Cartilagem Elástica/metabolismo , Cartilagem Hialina/transplante , Regeneração , Engenharia Tecidual/métodos , Animais , Autoenxertos , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Condrócitos/metabolismo , Condrogênese/genética , Cães , Regulação da Expressão Gênica , Glicosaminoglicanos/metabolismo , Cartilagem Hialina/citologia , Cartilagem Hialina/metabolismo , Masculino , Regeneração/genética , Fatores de TempoRESUMO
Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme responsible for the degradation of poly(ADP-ribose). PARG dysfunction sensitizes cells to alkylating agents and induces cell death; however, the details of this effect have not been fully elucidated. Here, we investigated the mechanism by which PARG deficiency leads to cell death in different cell types using methylmethanesulfonate (MMS), an alkylating agent, and Parg(-/-) mouse ES cells and human cancer cell lines. Parg(-/-) mouse ES cells showed increased levels of γ-H2AX, a marker of DNA double strand breaks (DSBs), accumulation of poly(ADP-ribose), p53 network activation, and S-phase arrest. Early apoptosis was enhanced in Parg(-/-) mouse ES cells. Parg(-/-) ES cells predominantly underwent caspase-dependent apoptosis. PARG was then knocked down in a p53-defective cell line, MIAPaCa2 cells, a human pancreatic cancer cell line. MIAPaCa2 cells were sensitized to MMS by PARG knockdown. Enhanced necrotic cell death was induced in MIAPaCa2 cells after augmenting γ-H2AX levels and S-phase arrest. Taken together, these data suggest that DSB repair defect causing S-phase arrest, but p53 status was not important for sensitization to alkylation DNA damage by PARG dysfunction, whereas the cell death pathway is dependent on the cell type. This study demonstrates that functional inhibition of PARG may be useful for sensitizing at least particular cancer cells to alkylating agents.
Assuntos
Apoptose , Adutos de DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Glicosídeo Hidrolases/genética , Fase S , Alquilação , Animais , Antineoplásicos Alquilantes/farmacologia , Caspases/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Técnicas de Inativação de Genes , Glicosídeo Hidrolases/deficiência , Humanos , Potencial da Membrana Mitocondrial , Metanossulfonato de Metila/farmacologia , Camundongos , Mutagênicos/farmacologia , Poli Adenosina Difosfato Ribose/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme for degradation of poly(ADP-ribose) by splitting ribose-ribose bonds. Parg-deficient (Parg(+/-) and Parg(-/-)) mouse ES cell lines have been established by disrupting both alleles of Parg exon 1 through gene-targeting. A transcript encoding a full length isoform of Parg was eliminated and only low amounts of Parg isoforms were detected in Parg(-/-) embryonic stem (ES) cells. Poly(ADP-ribose) degradation activity was decreased to one-tenth of that in Parg(+/+) ES cells. Parg(-/-) ES cells exhibited the same growth rate as Parg(+/+) ES cells in culture. Sensitivity of Parg(-/-) ES cells to various DNA damaging agents, including an alkylating agent dimethyl sulfate, cisplatin, gemcitabine, 5-fluorouracil, camptothecin, and gamma-irradiation was examined by clonogenic survival assay. Parg(-/-) ES cells showed enhanced lethality after treatment with dimethyl sulfate, cisplatin and gamma-irradiation compared with wild-type (Parg(+/+)) ES cells (p<0.05, respectively). In contrast, a sensitization effect by Parg-deficiency was not observed with gemcitabine and camptothecin. These results suggest the possibility that functional inhibition of Parg leads to sensitization of tumor cells to some chemo- and radiation therapies.
Assuntos
Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos da radiação , Glicosídeo Hidrolases/fisiologia , Animais , Antineoplásicos/farmacologia , Northern Blotting , Western Blotting , Células Cultivadas , Cisplatino/farmacologia , Ensaio de Unidades Formadoras de Colônias , Raios gama , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfetos/farmacologiaRESUMO
Carcinogenesis involves multiple steps and pathways with functional alterations in a variety of genes. There is accumulating evidence that a deficiency of poly(ADP-ribose) polymerase (PARP)-1 leads to DNA repair defects, genomic instability, failure of induction of cell death and modulation of gene transcription. PARP-1 also supports the growth of tumor cells in certain situations. Genetic analyses of the PARP-1 gene have demonstrated alterations in neoplasms, and a mutation affecting the conserved amino acid E251 in germ cell tumors, as well as an association of a single-nucleotide polymorphism V762A with risk of prostate cancer. Recent development of a selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), the enzyme primarily responsible for degradation of poly(ADP-ribose), and PARG-deficient animals should facilitate studies of the relationship of poly(ADP-ribose) with carcinogenesis. Inhibitors of PARP have also suggested roles in the pathogenesis of autoimmune disease, and a promoter haplotype of PARP-1 confers a higher risk of rheumatoid arthritis. Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases. Furthermore, there is potential for sensitization to chemo- and radiation therapy of cancers as well as the treatment of autoimmune disease with development of stronger PARP inhibitors.
Assuntos
Doenças Autoimunes/metabolismo , Glicosídeo Hidrolases/metabolismo , Neoplasias/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Morte Celular , Reparo do DNA , Inibidores Enzimáticos/farmacologia , Instabilidade Genômica , Glicosídeo Hidrolases/antagonistas & inibidores , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , Ativação TranscricionalRESUMO
One of the most important local adaptations to pregnancy is the change in maternal blood flow to the implantation site. In rodents and primates, new blood vessels form through angiogenesis, dilate and then become modified such that the blood enters into trophoblast cell-lined sinuses (hemochorial). Evidence from gene knockout mice suggests that factors from the placenta regulate the uterine vasculature. Consistent with this, trophoblast giant cells produce a number of angiogenic and vasoactive substances that may mediate these effects. Teratocarcinomas containing large numbers of trophoblast giant cells (derived from Parp1 gene-deficient ES cells) show similar 'hemochorial' host blood flow, implying that the effects are not specific to the uterine vascular bed. As in primates, murine trophoblast cells also invade into the uterine arteries of the mother. However, in normal pregnancy, dilation of the uterine arteries may be largely mediated by the effect of uterine natural killer cells.
Assuntos
Neovascularização Fisiológica , Placenta/irrigação sanguínea , Trofoblastos/fisiologia , Indutores da Angiogênese/fisiologia , Animais , Feminino , Humanos , Placenta/citologia , Circulação Placentária/fisiologia , Gravidez , Trofoblastos/citologia , Trofoblastos/metabolismo , Útero/irrigação sanguíneaRESUMO
Early gastric cancer can be macroscopically classified into elevated and depressed types. To clarify the relationship between macroscopic appearance of early gastric cancer and apoptosis or cell proliferation, formalin-fixed paraffin-embedded tissue specimens of 44 intestinal-type early gastric cancers were investigated by the TUNEL method and immunohistochemical techniques. Diffuse type was excluded in this study. When tissue sections of gastric cancer were vertically classified into the 3 compartments of luminar, intermediate and basal, the apoptosis index (%) was significantly higher in the basal compartment of depressed type (1.76 +/- 2.04, mean +/- SD) than in the basal compartment of elevated type (0.63 +/- 0.81, P = 0.01). In depressed type, the apoptosis index (%) was significantly higher in the basal compartment than in the luminar compartment (0.76 +/- 0.85, P = 0.03). Apoptosis-inducing protein, Bax, was expressed more in each of the compartments of depressed type than in those of elevated type, while there were no significant differences in expression of anti-apoptotic protein, Bcl-2, between the two types. Moreover, the apoptosis index (%) of Bax-positive gastric cancer was significantly higher in the basal compartment (P = 0.03), compared to that of Bax-negative gastric cancer, while there were no significant differences in apoptosis index (%) in any compartment between Bcl-2-positive and Bcl-2-negative gastric cancers. There were no significant differences in Ki-67 expression, either between the two types, or among the compartments of depressed type. These results indicate that increased apoptosis with excessive expression of Bax in the basal compartment is involved in the morphogenesis of the depressed type in intestinal-type early gastric cancer.
Assuntos
Apoptose , Neoplasias Gastrointestinais/patologia , Idoso , Divisão Celular , Feminino , Neoplasias Gastrointestinais/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2RESUMO
Autologous stem cell transplantation is used widely after high-dose chemotherapy for treating hematological and other malignancies. Bone marrow harvested for autologous bone marrow transplantation may contain residual malignant cells even when the cancer is judged to be in remission. Attempts to purge marrow of its putative residual malignant cells may delay hemopoietic reconstitution and are of uncertain efficacy. In this report, we demonstrate the possibility of applying hypothermia to autologous stem cell purging. Using clonogenic assay, we compared the surviving fraction of human leukemia (HL60, K562) and human small cell lung cancer (H69) cell lines with that of normal human bone marrow CFU-GM and BFU-E cells after incubation at 4 +/- 0.1 degrees C for 24 and 48 h. Hypothermia decreased the surviving fraction of HL60, H69, and K562 cells. In contrast, the surviving fractions of stem cells were not affected by the temperature shift. The surviving fraction of HL60 cells at 4 degrees C cooling was significantly lower than that at 22 degrees C cooling. These findings suggest that in vitro hypothermia may selectively purge residual malignant cells in stored remission bone marrow and may be applicable before autologous bone marrow transplantation. In addition, the method is very simple and cost effective.
Assuntos
Purging da Medula Óssea/métodos , Temperatura Baixa , Transplante de Células-Tronco Hematopoéticas , Células HL-60 , Humanos , Técnicas In Vitro , Células K562 , Transplante Autólogo , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-TroncoRESUMO
OBJECTIVES: Crohn's disease (CD) is recognized to be a vascular endothelial-associated disease. Angiotensin I-converting enzyme (ACE) exists mainly in endothelial cells. There are some reports on serum ACE levels in patients with CD, but the ACE level is still controversial. Recently, genetic control of serum ACE levels by ACE gene polymorphisms (classified as II, ID, and DD) has been suggested. Although we must consider such polymorphisms to elucidate ACE levels in patients with CD, there is no report about this. METHODS: We studied 341 healthy controls (male/female = 178/162), 39 patients with CD (31/8), 43 patients with ulcerative colitis (UC) (22/21) and 19 patients with infectious enterocolitis (8/11). The polymorphism in intron 16 of the ACE gene was examined by PCR. Serum ACE levels were measured by the method of Kasahara. RESULTS: Serum ACE levels in patients with CD and UC were significantly lower than in healthy controls, irrespective of the genotype of ACE (genotype II: CD 7.0+/-2.5 [mean +/- SD], UC 7.1+/-3.3, controls 11.8+/-2.9, genotype ID: CD 9.7+/-4.1, UC 11.4+/-4.6, controls 15.2+/-3.6, genotype DD: CD 13.9+/-5.8, UC 10.7+/-3.6, controls 19.3+/-3.9 IU/L, controls vs CD, UC; p < 0.01, 0.05). However, there was no significant difference in serum ACE levels between CD and UC. CONCLUSIONS: Considering ACE gene polymorphism, serum ACE levels in patients with inflammatory bowel disease are lower than in controls. Serum ACE levels reflect a part of the pathogenesis of inflammatory bowel disease.
Assuntos
Colite Ulcerativa/sangue , Colite Ulcerativa/genética , Doença de Crohn/sangue , Doença de Crohn/genética , Peptidil Dipeptidase A/sangue , Adulto , Feminino , Genótipo , Humanos , MasculinoAssuntos
Adenocarcinoma/patologia , Tumor Carcinoide/patologia , Gastroscopia/métodos , Segunda Neoplasia Primária/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/cirurgia , Idoso , Biópsia por Agulha , Endoscopia , Seguimentos , Humanos , Masculino , Fotomicrografia , Neoplasias Gástricas/cirurgiaRESUMO
Poly(ADP-ribose) polymerase (Parp) monitors DNA strand breaks and poly(ADP-ribosyl)ates nuclear proteins using NAD as a substrate. The participation of Parp in DNA damage responses has been demonstrated by recent studies using Parp knockout mice. On the other hand, accumulated evidence has shown that Parp is involved in the regulation of gene expression and cell differentiation. In this study, the role of Parp in tumorigenesis and differentiation was studied with Parp-/- embryonic stem (ES) cells. When Parp+/+, Parp+/-, and Parp-/- ES cells were injected subcutaneously into nude mice, teratocarcinoma-like tumors developed from ES cells. However, only tumors derived from Parp-/- ES cells showed trophoblast giant cells (TGCs) containing single or multiple megalo-nuclei. These TGCs are located in a large blood-lake like hemorrhage. This example suggests that Parp is not essential for tumor formation, however, it is involved in trophoblastic cell differentiation and could consequently affect tumor phenotype.
Assuntos
Diferenciação Celular , Transformação Celular Neoplásica , Poli(ADP-Ribose) Polimerases/fisiologia , Trofoblastos/patologia , Animais , Camundongos , Células-Tronco , Trofoblastos/citologiaRESUMO
The involvement of poly(ADP-ribose) polymerase-1 (Parp-1), one of the poly(ADP-ribose) polymerase family proteins, in genomic stability, DNA repair and cell death triggered by DNA damage has been well documented. However, the potential role of Parp-1 in carcinogenesis has not been well evaluated. In this study the carcinogenic activity of N:-nitrosobis(2-hydroxypropyl)amine (BHP) was studied in Parp-1(-/-) mice, generated by disrupting P:arp-1 gene exon 1. Parp-1(-/-) and Parp-1(+/+) male mice received 0, 250 and 500 p.p.m. BHP in their drinking water for 20 weeks and were then killed. The percentage of animals bearing hemangiomas and hemangiosarcomas in the liver and numbers of tumors per mouse were markedly higher in the Parp-1(-/-) groups given 250 or 500 p.p.m. BHP than in their Parp-1(+/+) counterparts. Hemangiosarcomas developed only in Parp-1(-/-) mice. In the lung the numbers of adenomas per mouse were increased in Parp-1(-/-) mice given BHP at 250 and 500 p.p.m. (P < 0.01) compared with the Parp-1(+/+) case. The results show that susceptibility to BHP is significantly elevated in Parp-1(-/-) mice, thus providing direct evidence that Parp-1 is relevant to carcinogenesis.
Assuntos
Carcinógenos/toxicidade , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Pulmonares/enzimologia , Nitrosaminas/toxicidade , Poli(ADP-Ribose) Polimerases/metabolismo , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/enzimologia , Adenoma/induzido quimicamente , Adenoma/enzimologia , Animais , Testes de Carcinogenicidade , Suscetibilidade a Doenças/enzimologia , Hemangioma/induzido quimicamente , Hemangioma/enzimologia , Hemangiossarcoma/induzido quimicamente , Hemangiossarcoma/enzimologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Poli(ADP-Ribose) Polimerases/genéticaRESUMO
We investigated the effect of Adriamycin on FL-amnion (FL) cells. After treatment with the drug, the cells arrested at G2, but we did not detect an increase in the p21 levels. We established a p53-deficient derivative of these cells, in which G2 arrest also occurred after treatment with Adriamycin, suggesting that the arrest we observed in these cells is independent of the p53 pathway. Low doses of Adriamycin (100-200 ng/ml) induced G2 arrest, while late S-phase arrest was observed at high doses (500-1000 ng/ml) in both FL and p53-deficient FL cells. Accumulation of cyclin B1 was detected only in cells arrested at G2, and not in those arrested at S phase, suggesting that the S-phase checkpoint functioned efficiently even in p53-deficient FL cells. In both cell lines, caffeine-induced activation of CDC2 kinase was detected only in cells arrested at G2 and CDC2 kinase-activated cells died exhibiting features of apoptosis. CDC2 kinase activation was inhibited by cycloheximide. Furthermore, cycloheximide inhibited activation of CDK2:cyclin A, which normally precedes CDC2 kinase activation in caffeine-treated cells. These results suggest that p53 and p21 do not have special roles in the S- and G2-phase checkpoints and that CDK2:cyclin A could be the target of the G2-phase DNA damage checkpoint.
Assuntos
Âmnio/efeitos dos fármacos , Cafeína/farmacologia , Ciclinas/fisiologia , Doxorrubicina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Proteínas Repressoras , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/fisiologia , Âmnio/metabolismo , Apoptose , Proteína Quinase CDC2/metabolismo , Ciclina B/metabolismo , Ciclina B1 , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Cicloeximida/farmacologia , Dano ao DNA , Ativação Enzimática , Fase G2 , Humanos , Proteínas Oncogênicas Virais/genética , Inibidores da Síntese de Proteínas/farmacologia , Fase S , Transfecção , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Brain (B-type) natriuretic peptide (BNP) is known to be secreted predominantly from the myocardium. Brain natriuretic peptide plasma concentrations have been shown to be markedly increased in patients with acute myocardial infarction; however, plasma BNP response during episodes of myocardial ischemia has not been established. HYPOTHESIS: This study was designed to examine plasma BNP in patients with transient myocardial ischemia induced by inflation of a percutaneous transluminal coronary angioplasty (PTCA) balloon. METHODS: Thirty consecutive patients (26 men and 4 women; mean age 61 years) who underwent PTCA, and another 49 patients (39 men and 10 women; mean age 63 years) who underwent diagnostic coronary angiography were enrolled in this study. Serum BNP concentrations were assayed in all patients. RESULTS: Plasma BNP was increased significantly with a peak concentration of 66.1 +/- 65.2 pg/ml 24 h after PTCA. Coronary angiography did not cause plasma BNP increase (immediately before 30.4 +/- 29.0 pg/ml, 24 h after 33.7 +/- 30.6 pg/ml). No significant differences were present in hemodynamic parameters measured immediately before and 24 h after PTCA. CONCLUSION: Plasma BNP is increased by transient myocardial ischemia induced by PTCA.
Assuntos
Angioplastia Coronária com Balão , Peptídeo Natriurético Encefálico/sangue , Adolescente , Adulto , Idoso , Análise de Variância , Angina Pectoris/sangue , Angina Pectoris/diagnóstico , Angina Pectoris/terapia , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/métodos , Angiografia Coronária/métodos , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/etiologia , Fatores de TempoRESUMO
BACKGROUND: With the recent development of minimal treatment for early stage gastric carcinoma, identifying specific indicators of the metastatic potential of primary tumors has become more important. Cathepsin B and cathepsin L, both lysosomal cysteine proteases, degrade the extracellular matrix during tumor progression. Although many studies have shown their relation to human cancer progression, little is known about their roles in the early stage. The clinicopathologic significance of cathepsins was therefore studied in early stage gastric carcinoma. METHODS: Expression of both cathepsins was studied immunohistochemically in 51 tissue specimens from gastric carcinomas that invaded the submucosal layer or muscularis propria. The relation between their expression and clinicopathologic factors was analyzed. RESULTS: Both cathepsins were expressed at higher levels in tumors that invaded the muscularis propria than in those within the submucosa (P < 0.05). In addition, tumors with lymphatic invasion showed higher cathepsin B expression than those without it (P < 0.05), whereas tumors with venous invasion showed higher cathepsin L expression than those without it (P < 0.05). No other clinicopathologic factors correlated with expression of either cathepsin. CONCLUSIONS: Tumors with overexpression of cathepsins have powerful potential for invasiveness in the early stage of gastric carcinoma. Moreover, the authors hypothesize that cathepsins may be one of the determinants of the metastatic route. To the authors' knowledge, this is the first report on specific proteases concerning the mode of metastasis, and the results of this study suggest that therapeutic strategies for early stage gastric carcinoma might need to be changed according to the status of cathepsins.
Assuntos
Catepsina B/metabolismo , Catepsinas/metabolismo , Endopeptidases , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Carcinoma/patologia , Catepsina L , Cisteína Endopeptidases , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade NeoplásicaRESUMO
Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have identified the various roles of Parp in cellular responses to DNA damage. The partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mutant mice indicates the participation of Parp in the repair of DNA strand break. Parp(-/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is also thought to be involved in base-excision repair after DNA damage caused by alkylating agents. On the other hand, resistance of Parp(-/-) mice to DNA damage induced by reactive oxygen species implicates the contribution of Parp to cell death through NAD depletion. Parp(-/-) mice with two different genetic backgrounds also show enhanced sensitivity to the lethal effects of gamma-irradiation. Parp(-/-) mice show more severe villous atrophy of the small intestine compared to the wild-type counterpart in a genetic background of 129Sv/C57BL6. Other forms of enhanced tissue damage have been identified in Parp(-/-) mice with a genetic background of 129Sv/ICR. For example, Parp(-/-) mice exhibit extensive hemorrhage in the glandular stomach and other tissues, such as the testes, after gamma-irradiation. Severe myelosuppression is also observed in both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive extramedullary hematopoiesis in the spleen during the recovery phase of post-irradiation, whereas the spleen of Parp(-/-) mice exhibits severe atrophy with no extramedullary hematopoiesis. The absence of extramedullary hematopoiesis in the spleen is probably the underlying mechanism of hemorrhagic tendency in various tissues of Parp(-/-) mice. These findings suggest that loss of Parp activity could contribute to post-irradiation tissue hemorrhage.
Assuntos
Alquilantes/administração & dosagem , Dano ao DNA , DNA/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/genética , Animais , Morte Celular , DNA/genética , Reparo do DNA , Mucosa Gástrica/metabolismo , Masculino , Metanossulfonato de Metila/administração & dosagem , Metilnitrosoureia/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Endogâmicos , Camundongos Knockout , Camundongos SCID , Mutação , NAD/metabolismo , Poli(ADP-Ribose) Polimerases/fisiologia , Baço/metabolismo , Baço/patologia , Baço/efeitos da radiação , Estômago/patologia , Estômago/efeitos da radiação , Análise de Sobrevida , Testículo/metabolismo , Testículo/patologia , Testículo/efeitos da radiaçãoRESUMO
Many recent studies have demonstrated that tumour angiogenesis is a potent prognostic factor for various malignant tumours, but this has not been clearly shown in non-small cell lung carcinoma (NSCLC). The purpose of this study was to re-evaluate the prognostic value of MVD associated with VEGF in patients with NSCLC by comparing the immunohistochemical results obtained for CD34 with those obtained for vWf. Microvessel density (MVD) and the expression of vascular endothelial growth factor (VEGF) were investigated in 108 cases of NSCLC by immunohistochemistry. The correlation between von Willebrand factor (vWf) and CD34 staining for MVD was not strong, and vWf staining did not correlate with VEGF expression, but CD34 staining did. Staining for CD34 significantly correlated with survival in adenocarcinoma, distant metastasis and postoperative recurrence, but staining for vWf did not. CD34 was more sensitive and specific than vWf for staining endothelial cells associated with VEGF expression. It is suggested that research on neovascularisation should be investigated on every histological subtype or should focus on the early stages of NSCLC which are not under the influence of a variety of complications facilitating tumour neovascularisation.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Fatores de Crescimento Endotelial/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Linfocinas/metabolismo , Idoso , Antígenos CD34/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Microcirculação , Análise Multivariada , Metástase Neoplásica , Neovascularização Patológica/metabolismo , Prognóstico , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Fator de von WillebrandRESUMO
We conducted a randomized trial of dose-intensive weekly alternating chemotherapy (CAV/PE-W) and standard alternating chemotherapy (CAV/PE) in small cell lung cancer (SCLC) patients with good prognostic factors. A total of 76 patients with SCLC was randomized. The CAV/PE-W consisted of 4 alternating cycles of cyclophosphamide: 500 mg/m2, doxorubicin: 30 mg/m2, and vincristine: 1 mg/m2 (day 1) and cisplatin: 50 mg/m2 (day 8) and etoposide: 75 mg/m2 (days 8 and 9). The CAV/PE consisted of 2 alternating cycles of cyclophosphamide: 800 mg/m2, doxorubicin: 50 mg/m2, and vincristine: 1.4 mg/m2 (day 1), cisplatin: 100 mg/m2 (day 22) and etoposide: 100 mg/m2 (days 22, 23 and 24). Eligibility criteria were no prior therapy, no active concomitant malignancy, ECOG PS of 0 or 1, age < or =75, adequate hematologic functions and no brain metastasis. The complete response (CR) rate for CAV/PE-W (14/38, 36.8%) was significantly higher than that for CAV/PE (6/38, 15.8%, chi2; p=0. 032). However, the response rate in patients on CAV/PE-W (36/38, 94. 7%) was not significantly higher than the rate for CAV/PE (31/38, 81. 6%, chi2; p=0.076). Progression-free survival for patients on CAV/PE-W was significantly longer than that of patients on CAV/PE (41.4 weeks vs. 21.3 weeks, log-rank; p=0.0007, generalized Wilcoxon; p=0.0034) as was overall median survival (67.0 weeks vs. 51.2 weeks, log-rank; p=0.028). Actual dose-intensity of CAV/PE-W was 1.74 times that of CAV/PE. Hematological toxicities were equally frequent and G-CSF contributes to treatment efficacy by allowing administration of dose-intensive chemotherapy. The CAV/PE-W achieved a higher CR rate and longer survival, than the CAV/PE.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/fisiopatologia , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Vincristina/administração & dosagemRESUMO
OBJECTIVES: Ventricular tachycardia (VT) and ventricular fibrillation (Vf) induced in exercise stress testing should be treated urgently, although the occurrence of arrhythmia is rare. The conditions for the onset of arrhythmia and the clinical characteristics of VT and Vf patients in exercise stress testing were studied. METHODS: Fifty-nine patients (mean age 54 +/- 17 years, 41 males, 18 females) with VT (succession of 3 or more ventricular premature beats) or Vf induced in exercise stress testing were selected from 7,594 patients with consecutive treadmill stress testing in our hospital from January 1993 to February 1998. RESULTS: The incidence of exercise-induced VT or Vf was 0.8%, and there were no fatal accidents in all tests. Among the 59 patients with exercise-induced VT or Vf, 52 patients had non-sustained VT, 5 had sustained VT, and 2 had Vf. Of the 59 patients, 23 had rhythm or conduction disturbances, 14 had coronary artery disease, 13 had cardiomyopathy, and 9 had valvular heart disease. The VT or Vf incidence in coronary artery disease was 0.2%, and in valvular heart disease was 10.8%. VT or Vf occurred at over 80% of maximum heart rate exercise intensity in 40 patients, including 4 with sustained VT and 2 with Vf, of the 59 patients. Also, in 9 VT patients including the 4 sustained VT patients, VT occurred in the exercise recovery period within 2 min after the exercise. Although VT disappeared spontaneously in 52 non-sustained VT and 3 sustained VT patients, intravenous injection of lidocaine was needed in 2 sustained VT patients and direct current defibrillator was needed in 2 Vf patients. Furthermore, only one non-cardiac death was observed in the follow-up period of average 42 months. CONCLUSIONS: Our results showed clinical characteristics and incidence of VT or Vf similar to past reports. Furthermore, all sustained VT and Vf patients, who should be treated urgently, had a past history of ventricular premature beats or VT. Our data suggest that VT and Vf could occur during the recovery period, especially in patients with documented ventricular tachyarrhythmias when the stress intensity has reached the critical level in the exercise tolerance test.