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1.
Sci Rep ; 10(1): 6549, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300235

RESUMO

Many aspects of the supposed hyperthermal Toarcian Oceanic Anoxic Event (T-OAE, Early Jurassic, c. 182 Ma) are well understood but a lack of robust palaeotemperature data severely limits reconstruction of the processes that drove the T-OAE and associated environmental and biotic changes. New oxygen isotope data from calcite shells of the benthic fauna suggest that bottom water temperatures in the western Tethys were elevated by c. 3.5 °C through the entire T-OAE. Modelling supports the idea that widespread marine anoxia was induced by a greenhouse-driven weathering pulse, and is compatible with the OAE duration being extended by limitation of the global silicate weathering flux. In the western Tethys Ocean, the later part of the T-OAE is characterized by abundant occurrences of the brachiopod Soaresirhynchia, which exhibits characteristics of slow-growing, deep sea brachiopods. The unlikely success of Soaresirhynchia in a hyperthermal event is attributed here to low metabolic rate, which put it at an advantage over other species from shallow epicontinental environments with higher metabolic demand.


Assuntos
Adaptação Fisiológica , Hipóxia/fisiopatologia , Invertebrados/fisiologia , Oceanos e Mares , Temperatura , Animais , Ciclo do Carbono , Isótopos de Carbono , Geografia , Invertebrados/ultraestrutura , Modelos Teóricos , Isótopos de Oxigênio , Paleontologia
2.
Rev Sci Instrum ; 87(2): 02A705, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26931923

RESUMO

The high current ion source with the low energy beam transport (LEBT) will serve as injector into the proton LINAC to provide primary proton beam for the production of antiprotons. The pulsed ion source developed and built in CEA/Saclay operates with a frequency of 2.45 GHz based on ECR plasma production with two coils with 87.5 mT magnetic field necessary for the electron cyclotron resonance. The compact LEBT consists of two solenoids with a maximum magnetic field of 500 mT including two integrated magnetic steerers to adjust the horizontal and vertical beam positions. The total length of the compact LEBT is 2.3 m and was made as short as possible to reduced emittance growth along the beam line. To measure ion beam intensity behind the pentode extraction system, between solenoids and at the end of the beam line, two current transformers and a Faraday cup are installed. To get information about the beam quality and position, the diagnostic chamber with different equipment will be installed between the two solenoids. This article reports the current status of the proton injector for the facility of antiproton and ion research.

3.
Rev Sci Instrum ; 87(2): 02B938, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26932110

RESUMO

Experiments to investigate the space charge compensation of pulsed high-current heavy ion beams are performed at the GSI ion source text benches with a 4-grid analyzer provided by CEA/Saclay. The technical design of the 4-grid analyzer is revised to verify its functionality for measurements at pulsed high-current heavy ion beams. The experimental investigation of space charge compensation processes is needed to increase the performance and quality of current and future accelerator facilities. Measurements are performed directly downstream a triode extraction system mounted to a multi-cusp ion source at a high-current test bench as well as downstream the post-acceleration system of the high-current test injector (HOSTI) with ion energies up to 120 keV/u for helium and argon. At HOSTI, a cold or hot reflex discharge ion source is used to change the conditions for the measurements. The measurements were performed with helium, argon, and xenon and are presented. Results from measurements with single aperture extraction systems are shown.

4.
Rev Sci Instrum ; 85(2): 02A952, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24593531

RESUMO

The new international accelerator facility for antiproton and ion research (FAIR) at GSI in Darmstadt, Germany, is one of the largest research projects worldwide and will provide an antiproton production rate of 7 × 10(10) cooled pbars per hour. This is equivalent to a primary proton beam current of 2 × 10(16) protons per hour. For this request a high intensity proton linac (p-linac) will be built with an operating rf-frequency of 325 MHz to accelerate a 35 mA proton beam at 70 MeV, using conducting crossed-bar H-cavities. The repetition rate is 4 Hz with beam pulse length of 36 µs. The microwave ion source and low energy beam transport developed within a joint French-German collaboration GSI/CEA-SACLAY will serve as an injector of the compact proton linac. The 2.45 GHz ion source allows high brightness ion beams at an energy of 95 keV and will deliver a proton beam current of 100 mA at the entrance of the radio frequency quadrupole (RFQ) within an acceptance of 0.3π mm mrad (norm., rms).

5.
Pharmacol Res ; 58(5-6): 332-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18930148

RESUMO

OBJECTIVE: Among the complications after cardiac surgery the development of postoperative pulmonary distress is a serious problem. Typically, the patients leave the operating theatre with good blood gas values and O(2)-saturation, but develop their respiratory problems within the next hours/days. We investigated whether extracorporeal circulation may induce biochemical and histological changes in the lungs which may help to explain this development. METHODS: Piglets (6-10 kg) were anaesthetized using isoflurane and underwent extracorporeal circulation (ECC) with hypothermic (25-28 degrees C) cardioplegic arrest for 90 min followed by 3h reperfusion. An additional group received a poly(ADP-ribose) polymerase (PARP)-Inhibitor, INO1001. Cardiopulmonary monitoring was performed during the whole procedure. Finally, lungs were explanted and investigated by histomorphometry and immunohistology for heat shock protein HSP70 (indicator for cellular damage) and TNFalpha in comparison to normal piglets without ECC. RESULTS: Histologically we found significant swelling of the type I alveocytes (thickness increased from 2.4 to 3.2 microm), interstitial oedema, intra-alveolar erythrocyte (4.8 versus 0.4 erythrocytes/alveole) and granulocyte accumulation and fibrinous exudates. There was a significant up-regulation of TNFalpha and of the cellular repair enzyme HSP70, while in control piglets only minimal levels were observed. INO1001 significantly reduced ECC-induced elevation in TNFalpha and in HSP70. Despite the dramatic changes after heart-lung-machine (HLM), blood gases and gas transport were almost not affected at that time. CONCLUSIONS: ECC can lead to early significant histological and histochemical changes which have similarities with a beginning early stage shock lung, although - at 3h reperfusion - gas transport is still sufficient. INO1001 can partially antagonize these changes.


Assuntos
Circulação Extracorpórea/efeitos adversos , Indóis/farmacologia , Isquemia/tratamento farmacológico , Isquemia/patologia , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Inibidores de Poli(ADP-Ribose) Polimerases , Circulação Pulmonar/fisiologia , Animais , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Granulócitos/ultraestrutura , Proteínas de Choque Térmico HSP70/análise , Proteínas de Choque Térmico HSP70/biossíntese , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Consumo de Oxigênio/fisiologia , Alvéolos Pulmonares/patologia , Circulação Pulmonar/efeitos dos fármacos , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Suínos , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossíntese
6.
J Vet Med A Physiol Pathol Clin Med ; 54(5): 230-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17523955

RESUMO

Preserved ultrastructure is an important precondition for functional regeneration after heart transplantation. We investigated the effectiveness of a newly developed modified Langendorff system in extracorporeal heart perfusion. (Experiment I) Cardioplegia and cold ischaemia were performed in six pigs. Hearts were connected to a modified Langendorff system, and perfused with leucocyte depleted autologous blood. (Experiment II) The untreated hearts of three healthy pigs served as controls. Forty-seven myocardial biopsies at different timepoints (I: n = 29, II: n = 18) were investigated by transmission electronmicroscopy. Cardioplegia/hypothermia (I) induced mild-to-moderate mitochondrial swelling, mild myofibrillar degeneration in cardiomyocytes and moderate endothelial oedema. After 4 h reperfusion cardiomyocytes showed moderate myofibrillar and mild sarcolemmal damage. Moderate endothelial degeneration, mild interstitial oedema and haemorrhages appeared. Untreated hearts (II) showed severely damaged mitochondria and nuclei after 30 min while the myofibrillar structure remained unaffected until 4 h later. This is a promising model for extracorporeal heart perfusion. However, ultrastructural findings indicated that some necessary modifications to prevent cellular damages during reperfusion were needed.


Assuntos
Traumatismo por Reperfusão Miocárdica/veterinária , Reperfusão Miocárdica/veterinária , Miocárdio/patologia , Miocárdio/ultraestrutura , Preservação de Órgãos/veterinária , Animais , Feminino , Transplante de Coração/veterinária , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Preservação de Órgãos/métodos , Soluções para Preservação de Órgãos/farmacologia , Distribuição Aleatória , Suínos , Fatores de Tempo
7.
Neurosci Lett ; 375(3): 192-7, 2005 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-15694259

RESUMO

Increased hippocampal excitability constitutes a pathogenetic hallmark of pharmacoresistant human temporal lobe epilepsy (TLE). Metabotropic glutamate receptors (mGluRs) can be subdivided into three classes based on sequence homologies, mechanisms of signal transduction as well as pharmacological characteristics. Generally, class I mGluRs mediate neuronal excitation whereas activation of class II and III mGluRs decreases synaptic transmission. Changes in expression of class I and III mGluR subunits have been described in human TLE. It remains to be determined whether altered mGluR expression relates to differences in seizure susceptibility or hippocampal damage. Here, we examine the transcription levels of mGluRs class I (mGluR1 and 5) and III (mGluR4 and 7) in experimental TLE and correlate differential mGluR subunit expression with mouse-strain-dependent susceptibility to TLE induced by pilocarpine. Expression of mGluRs 1, 4, 5 and 7 was determined in epileptic dentate gyrus granule cells (DG) in CD1, C57BL/6 and FVB/N mice by real time RT-PCR. FVB/N mice appear significantly more vulnerable to pilocarpine-induced seizures than C57BL/6 and CD1 strains. RT-PCR analysis demonstrates an increased expression of inhibitory mGluR 4 and downregulation of excitatory mGluR 1 in epileptic CD1 mice and a decrease of the excitatory mGluRs 1 and 5 in C57BL/6 (p<0.05, n=6 each) but not in the FVB/N strain. These results correlate differential expression of excitatory class mGluR I and inhibitory class mGluR III to seizure susceptibility and hippocampal damage. Our data suggest mGluRs class I and III as interesting potential therapeutic targets to interfere with hippocampal epileptogenesis and hyperexcitability.


Assuntos
Epilepsia do Lobo Temporal/induzido quimicamente , Regulação da Expressão Gênica , Pilocarpina , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Regulação da Expressão Gênica/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos , Agonistas Muscarínicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Especificidade da Espécie
8.
Thorac Cardiovasc Surg ; 51(5): 267-73, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14571343

RESUMO

BACKGROUND: The purpose of this study was to test the feasibility and effectiveness of cryoablation therapy (SurgiFrost trade mark CryoCath, Endocare Inc., Irvine, California, USA) for linear epicardial treatment of atrial fibrillation in an acute off-pump sheep model. METHODS: After thoracotomy, we performed epicardial cryoablation (2 min intervals at -160 degrees C) with pacing electrodes positioned at the left atrial appendage (LAA), the pulmonary veins (PVs), the right atrial appendage (RAA), and the vena cava cranialis (VCC) in 8 sheep. Circular epicardial ablations were performed with online temperature measurement in the ascending aorta and in the esophagus. The sheep were sacrificed two hours after ablation procedure, and heart, lungs, and esophagus were retrieved for histological examination. Out of all 8 sheep, histo-pathological analysis was performed on the RAA and VCC in 6 sheep and on the CAA and PV in all 8 sheep. RESULTS: Thin-walled structures such as PVs and VCC showed electrical isolation. No significant changes in temperature in the descending aorta and the esophagus were observed. There was evidence of extensive transmural alteration including vascular lesions, myocardial degeneration and necrosis as well as epi- and endocardial necrosis in the left atria in three of 8 cases, in the right atria in 5 of 6 cases, in the VCC in 6 of 6 cases, and in the PV in 5 of 8 cases. Mild lesions of the muscular layer of the esophagus were found in 7 of 8 cases. CONCLUSIONS: Epicardial cryoablation is not effective on thicker tissues like LAA and RAA due to the rewarming of the current blood flow. However, thin tissues like VCC and PV can be isolated. Further chronic studies are necessary to evaluate the potential for regeneration of adjacent structures.


Assuntos
Apêndice Atrial/patologia , Fibrilação Atrial/terapia , Criocirurgia/instrumentação , Veias Pulmonares/patologia , Veia Cava Superior/patologia , Animais , Estudos de Viabilidade , Humanos , Modelos Animais , Pericárdio/patologia , Ovinos , Resultado do Tratamento
9.
Drug Metab Dispos ; 31(6): 714-7, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12756202

RESUMO

The bladder spasmolytics propiverine was shown to induce hepatic cytochrome P450 (P450) and aminopyrine and aniline oxidation in rats. To characterize the type of enzyme induction and its dose dependence, activities of seven hepatic microsomal P450-dependent monooxygenases were measured in 72 male LEW1A albino rats (body weight 236-295 g) after oral treatment with 0.5, 2, 6, and 60 mg/kg of propiverine hydrochloride for 5 days and compared with the effects of 40 mg/kg beta-naphthoflavone, 10 mg/kg phenobarbital, and 20 mg/kg dexamethasone (each group, n = 8). CYP2B expression was measured by Western blotting. Furthermore, the inhibitory potency of propiverine on P450 enzymes was evaluated in competition assays with three most specific monooxygenases. Results show that Propiverine induced several monooxygenases and CYP2B expression dose dependently. The effects were well comparable with a phenobarbital-type inducer with 60 mg/kg being equipotent to 10 mg/kg phenobarbital. Furthermore, propiverine in low concentrations inhibited pentylresorufin O-dealkylase (for CYP2B) in vitro. In conclusion, propiverine is a phenobarbital-type inducer on hepatic P450 enzymes in rats in doses about 100-times above the therapeutic doses in man.


Assuntos
Benzilatos/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Animais , Hidrocarboneto de Aril Hidroxilases/biossíntese , Western Blotting , Inibidores das Enzimas do Citocromo P-450 , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Eletroforese em Gel Bidimensional , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Masculino , Fenobarbital/farmacologia , Ratos , beta-Naftoflavona/farmacologia
10.
Artif Organs ; 25(5): 327-30, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11403659

RESUMO

As coronary artery bypass grafting (CABG) surgery in the beating heart technique is progressing, new devices have been developed to overcome hemodynamic instabilities while tilting the heart for exposure of back wall vessels. A new device for in heart biventricular intracorporeal circulation was applied in 42 patients undergoing CABG surgery (Group 1). The control group consisted of 38 patients operated on using a conventional cardiopulmonary bypass setup (Group 2). The study protocol of the prospective, randomized multicenter study was approved by the local ethics committees. Patients were included following inclusion criteria and patient informed consent. Mean age, procedure time, mean arterial pressure (MAP), and hemolysis by means of plasma free hemoglobin (fHb) were assessed preoperatively, perioperatively, on postoperative Days 1 to 3, at discharge, and at a 3 month follow-up. The mean age was 62.1 (range 59-74) years (Group 1), 62.7 (range 48-72) years (Group 2); procedure time was 112 min +/- 31.9 min (Group 1), 137.4 min +/- 36.2 min (Group 2); and 2.3 +/- 0.6 (Group 1), 2.2 +/- 0.7 (Group 2), vessels were revascularized. The flow on pump was 3.7 (2.5/4.4) L/min (Group 1), 4.9 (3.6/6.2) L/min (Group 2) which resulted in a MAP of 69.8 (4.0/143) mm Hg (Group 1), 58.3 (5.3/94) mm Hg while assessing the vessels of the back wall. Hemolysis defined by fHB was lower than 20 mg/dl at all times pre- and postoperatively. Intraoperative maximum values were up to 100 mg/dl in 4 patients (2 in Group 1 and 2 in Group 2). Body mass index was 26.4 +/- 2.6 (Group 1), 27.9 +/- 3.2. New York Heart Association Class was II to III in both groups. There were no pump related life threatening or severe adverse events. Beating heart procedures with ICC can be reliably and safely achieved. As the device is easy to use, it may deserve a more widespread use in the future.


Assuntos
Ponte de Artéria Coronária , Coração Auxiliar , Idoso , Bilirrubina/sangue , Contagem de Células Sanguíneas , Creatinina/sangue , Coração Auxiliar/efeitos adversos , Hemoglobinas/análise , Hemólise , Humanos , Período Intraoperatório , Pessoa de Meia-Idade , Estudos Prospectivos
11.
J Am Soc Echocardiogr ; 14(1): 11-9, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11174429

RESUMO

OBJECTIVE: We sought to image coronary arteries in excised hearts. METHODS: Twelve excised pigs' hearts were imaged in a water bath. The aortic valve was closed surgically. A contrast agent (Echovist) was injected into the aortic root and selectively into single coronary arteries. Three-dimensional (3D) imaging was performed with TomTec Echoscan equipment. Mechanical rotations were performed at 1 degrees intervals. The hearts were visualized by InVivo software. Selective coloring of coronary arteries in 3D data sets was obtained by using color superpositioning, which differentiates information before and after injection of contrast. Distance measurements were performed in conventional 3D echocardiograms of coronary arteries and color-superimposed echocardiograms and compared with those from angiograms and casts. RESULTS: After a learning curve, during which optimal conditions for the visualization of coronary arteries were determined, a quick display of all major parts of the coronary tree was obtained. Distance measurements (n >400) revealed that fundamental contrast echocardiography overestimated angiography by 25% +/- 5% and casts by 28% +/- 6%. However, distances in color-superimposed echocardiograms (flow mode 4) were not significantly different from those obtained from angiograms and casts. In harmonic contrast echocardiograms, color super-positioning gave smaller distances compared with those from fundamental contrast echocardiograms, though they were still significantly larger than the reference diameters. CONCLUSIONS: The 3D imaging of epicardial coronary arteries under ideal conditions in a water bath seems feasible and provides insight into coronary visualization with the use of ultrasonography.


Assuntos
Vasos Coronários/diagnóstico por imagem , Ecocardiografia Tridimensional , Processamento de Imagem Assistida por Computador , Animais , Artérias/diagnóstico por imagem , Meios de Contraste , Angiografia Coronária , Técnicas In Vitro , Polissacarídeos , Suínos
12.
J Mol Cell Cardiol ; 32(2): 197-208, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10722797

RESUMO

Ischemia/reperfusion leading to myocyte cell death has been reported as either necrotic or apoptotic or a combination of both. The importance of necrosis is well established but the role of apoptosis and the time of initiation are still unknown. Normothermic global ischemia of either 45 or 90 min duration followed by 6 h of reperfusion were induced in isolated canine hearts. After 45 min of ischemia, left ventricular function and adenine nucleotide (AN) content had recovered during reperfusion indicating reversible injury. DNA fragmentation determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was absent as was the 85 kDa fragment of poly-(ADP-ribose) polymerase (PARP). After 90 min of ischemia, electron microscopy indicated necrotic cell death in 90% of myocytes. Recovery of function and AN content during reperfusion was minimal. At the end of ischemia, caspase-3 was activated in 30% of all myocytes and PARP 85 kDa fragments were present by Western blot, indicating initiation of the apoptotic cascade. Lamin-B(1)labeling was significantly reduced from 90% in myocytes in control and ischemia to 30% in early reperfusion. Completion of apoptosis seen by TUNEL was evident in late reperfusion (7.6% of myocytes and 8.3% of non-myocytes). Experiments with 6 h ischemia without reperfusion showed absence of DNA fragmentation. We conclude that apoptotic cell death is initiated by ischemia but that reperfusion is needed for completion of the apoptotic cascade. Furthermore, it is concluded that cell death in acute global ischemia followed by reperfusion occurs predominantly by necrosis and that apoptosis is of minor importance in this pathophysiological situation.


Assuntos
Apoptose , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Nucleotídeos de Adenina/análise , Animais , Caspase 3 , Caspases/análise , Cromatografia Líquida de Alta Pressão , Fragmentação do DNA , Cães , Metabolismo Energético , Ativação Enzimática , Feminino , Células HL-60/enzimologia , Humanos , Marcação In Situ das Extremidades Cortadas , Lamina Tipo B , Laminas , Masculino , Miocárdio/química , Necrose , Proteínas Nucleares/análise , Poli(ADP-Ribose) Polimerases/análise , Função Ventricular Esquerda
13.
J Clin Oncol ; 16(8): 2752-60, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9704728

RESUMO

PURPOSE: We performed a phase I trial to determine whether in vivo expansion of activated CD4+ T cells was possible in cancer patients. 111Indium labeling was used to observe trafficking patterns of the infused stimulated CD4+ T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphoma received CTX at 300 or 1,000 mg/m2 intravenously (i.v.). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4+ T cells was obtained by negative selection. The CD4+ T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m2/d) by continuous infusion for 7 days. RESULTS: The absolute number of CD4+, CD4+/DR+, and CD4+/CD45RO+ T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of 111Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented. CONCLUSION: CD4+ T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkin's lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4+ T-cell expansion.


Assuntos
Antineoplásicos/administração & dosagem , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Ciclofosfamida/administração & dosagem , Imunoterapia Adotiva , Interleucina-2/administração & dosagem , Ativação Linfocitária , Adulto , Idoso , Terapia Combinada , Feminino , Humanos , Radioisótopos de Índio , Infusões Intravenosas , Leucaférese , Masculino , Pessoa de Meia-Idade
14.
Blood ; 89(7): 2529-36, 1997 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-9116299

RESUMO

The infusion of anti-CD3-activated murine T cells plus interleukin-2 (IL-2) exerts antitumor effects against several tumors in murine immunotherapy models. This study compares the therapeutic efficacy of anti-CD3-activated CD4+ or CD8+ T-cell subsets, when given with cyclophosphamide (Cy) and liposome-encapsulated IL-2 (L-IL2) in a murine model. C57BL/6 mice bearing subcutaneous (S.C.) MC-38 colon adenocarcinoma, 3LL Lewis lung carcinoma, or 38C13 lymphoma for 7 to 14 days were pretreated with low-dose intraperitoneal (I.P.) Cy before intravenous (I.V.) injection of anti-CD3-activated T cells or T-cell subsets. Cell administration was followed by I.P. administration of L-IL2 for 5 days. Mice receiving activated CD4+ T cells showed significantly reduced tumor growth or complete remissions with prolonged disease-free survival in MC-38, 3LL, and 38C13. The timing of Cy doses in relation to adoptive transfer was critical in obtaining the optimal antitumor effect by CD4+ cells. Injecting Cy 4 days before the infusion of CD4+ cells greatly enhanced the antitumor effect of the CD4+ cells and improved survival of the mice compared with other Cy regimens. C57BL/6 mice cured of MC-38 after treatment with CD4+ T cells developed tumor-type immunologic memory as demonstrated by their ability to reject rechallenges with MC-38, but not 3LL. Similarly, mice cured of 3LL tumors rejected rechallenges of 3LL, but not MC-38. The immunologic memory could be transferred with an I.V. injection of splenocytes from mice cured of MC-38 or 3LL. No cytotoxic T-lymphocyte activity was detected in T cells or T-cell subsets from mice cured of MC-38 or 3LL. Increased IL-2 and interferon-gamma (IFN-gamma) production was observed from CD4+ subsets in cured animals when stimulated in vitro with the original tumor, but not with an unrelated syngeneic tumor. These results suggest that tumor-specific immunity can be achieved in vivo with anti-CD3-stimulated CD4+ T cells in this cellular therapy model.


Assuntos
Adenocarcinoma/terapia , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD4-Positivos/transplante , Carcinoma Pulmonar de Lewis/terapia , Neoplasias do Colo/terapia , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Imunoterapia Adotiva , Interleucina-2/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Terapia Combinada , Esquema de Medicação , Feminino , Memória Imunológica , Interleucina-2/administração & dosagem , Lipossomos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL
15.
Cell Tissue Res ; 287(3): 583-90, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9023087

RESUMO

In ischaemic porcine myocardium, the growth of collateral vessels by angiogenesis is observed in clusters in the vicinity of focal necroses. Because mitosis of endothelial cells is a prerequisite for angiogenesis, the purpose of this study has been to evaluate the time course of mitosis as an indicator of vascular growth in a porcine model of coronary microembolization. Ischaemia was induced by injection of 25-microm microspheres in the left circumflex artery, followed by tissue collection from non-ischaemic and ischaemic areas of the same heart after 24, 72 or 168 h microembolization. Tissue was studied by histone H3 in-situ hybridization, PCNA/cyclin immunohistochemistry and electron microscopy. The number of blood vessels in ischaemic myocardium was compared with that in normal control tissue. Capillary growth started as early as 24 h after microembolization, as indicated by increasing numbers of proliferating, histone H3- and PCNA/cyclin-positive cells in the necrotic inflammatory foci of the ischaemic area. At 72 h and 168 h, the number of blood vessels was significantly higher in ischaemic than in normal myocardium, whereas at 168 h, mitosis of cells was, as in normal myocardium, a rare event. Coronary microembolization of porcine myocardium thus leads to an increased cellular proliferation rate between 24 h and less than 7 days after the onset of microembolization, followed by enhanced capillary growth. In-situ hybridization with histone H3 and PCNA/cyclin immunohistochemistry seem to be reliable markers for proliferation and vascular growth in non-cancerogenic tissue.


Assuntos
Vasos Coronários/fisiologia , Embolia/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Animais , Divisão Celular/fisiologia , Estudos de Avaliação como Assunto , Expressão Gênica/fisiologia , Histonas/análise , Histonas/genética , Imuno-Histoquímica , Hibridização In Situ , Intestino Delgado/química , Intestino Delgado/fisiologia , Microcirculação/fisiologia , Microscopia Eletrônica , Mitose/fisiologia , Fibras Musculares Esqueléticas/química , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/ultraestrutura , Antígeno Nuclear de Célula em Proliferação/análise , Antígeno Nuclear de Célula em Proliferação/genética , RNA Mensageiro/análise , Fase S/fisiologia , Suínos , Fatores de Tempo
17.
Cytokine ; 7(2): 118-29, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7780031

RESUMO

When administered as single agents, both interferon gamma (IFN-gamma) and interleukin 6 (IL-6) significantly increase carcinoembryonic antigen (CEA) and HLA class I antigen expression on the surface of human colorectal tumour cells. Studies were carried out to determine whether by combining those cytokines a synergistic enhancement of CEA and HLA expression could result. The findings revealed that the administration of 20 units IFN-gamma along with 1.7 ng IL-6, concentrations of each cytokine that individually induced minimal antigenic changes, together synergistically increased CEA and HLA class I as well as induced qualitative changes in HLA expression on WiDr human colon carcinoma cells. The magnitude of the synergistic increases in CEA and HLA class I expression were reminiscent of the level of antigen augmentation observed when administering 20- to 100-fold higher amounts of each cytokine as a single agent. Also, the addition of IL-6 potentiated the IFN-gamma induction of HLA class II expression. The combined administration of IL-6 potentiated the IFN-gamma did not have any additive or synergistic effects on the growth suppression of those tumour cells. Interestingly, utilization of specific neutralizing antibodies for type I interferons abrogated the increases of CEA and HLA expression seen with IL-6 treatment alone or in combination with IFN-gamma. Moreover, reverse transcriptase/polymerase chain reaction analyses revealed a constitutive expression as well as a temporal increase of IFN-beta mRNA transcripts in colon tumour cells treated with IL-6. Therefore, the findings provide indirect evidence that IFN-beta production seems to play a critical role in the ability of IL-6 to upregulate antigen expression alone or in combination with IFN-gamma. These findings provide insight into cytokine combinations that synergistically upregulate tumour-associated and normal HLA antigen expression on the surface of human tumour cells. Those results provide the rationale for the combined use of such cytokines to heighten tumour cell recognition in monoclonal antibody- or cell-mediated-based immunotherapeutic approaches.


Assuntos
Antígeno Carcinoembrionário/biossíntese , Expressão Gênica/efeitos dos fármacos , Antígenos HLA-D/biossíntese , Antígenos de Histocompatibilidade Classe I/biossíntese , Interferon gama/farmacologia , Interleucina-6/farmacologia , Anticorpos Monoclonais/farmacologia , Linhagem Celular , Neoplasias do Colo , Neoplasias Colorretais , Sinergismo Farmacológico , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , Proteínas Recombinantes , Células Tumorais Cultivadas
18.
Dis Colon Rectum ; 37(2 Suppl): S100-5, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8313780

RESUMO

PURPOSE: This study was designed to determine whether the ability of interferon-gamma to upregulate the expression of a human tumor antigen improved the therapeutic efficacy of a radionuclide-conjugated monoclonal antibody. METHODS: Tumor xenografts of the moderately differentiated human colon tumor cell line HT-29 were grown in athymic mice. Constitutive levels of the human tumor antigen, tumor-associated glycoprotein-72, were measured before and after treatment with interferon-gamma. Antitumor effects of an 131I-labeled antitumor-associated glycoprotein-72 monoclonal antibody, CC49, were determined by measuring changes in tumor volumes in the respective groups of athymic mice. RESULTS: Interferon-gamma induced a time-dependent and dose-dependent increase in tumor-associated glycoprotein-72 expression in the HT-29 tumors. Immunohistochemical staining revealed a more homogeneous tumor-associated glycoprotein-72-positive tumor cell population in tumors isolated from mice treated for eight days with interferon-gamma, which accounted for the enhanced tumor localization of 131I-CC49 in mice. That experimental model was used to examine the antitumor effects of combining interferon-gamma with 131I-CC49. Administration of 300 microCi of 131I-CC49 to mice bearing HT-29 tumors induced a transient suppression of tumor growth. Conversely, a long-term, sustained HT-29 tumor growth suppression was achieved in mice given 300 microCi of 131I-CC49 and interferon-gamma. In fact, the cytokine/radioimmunoconjugate combination eradicated any evidence of tumor in approximately 30 percent of the mice. CONCLUSION: The ability of interferon-gamma to enhance tumor-associated glycoprotein-72 expression substantially augmented the antitumor effects of the radioimmunoconjugate. Those observations provide additional argument for use of a radioimmunoconjugate in combination with a cytokine to improve tumor diagnosis and therapy.


Assuntos
Neoplasias do Colo/terapia , Interferon gama/administração & dosagem , Radioimunoterapia , Animais , Anticorpos Monoclonais , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/radioterapia , Terapia Combinada , Feminino , Glicoproteínas/biossíntese , Glicoproteínas/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Proteínas Recombinantes , Células Tumorais Cultivadas
19.
Cancer Res ; 53(3): 600-8, 1993 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-8425194

RESUMO

The moderately differentiated human colon tumor cell line, HT-29, constitutively expresses low levels of the high molecular weight mucin, tumor-associated glycoprotein 72 (TAG-72), and the M(r) 180,000 carcinoembryonic antigen (CEA) when grown as s.c. tumors in athymic mice. We report that the in vivo administration of gamma-interferon (IFN-gamma) resulted in a time- and dose-dependent increase in both TAG-72 and CEA expression in the HT-29 tumors. Immunohistochemical staining revealed a more homogeneous TAG-72-positive tumor cell population after IFN-gamma. Furthermore, both anti-TAG-72 and anti-CEA monoclonal antibodies (MAbs) showed enhanced localization to the HT-29 tumors in mice treated with IFN-gamma. Using that experimental model, subsequent studies presented evidence showing that the combination of IFN-gamma with 131I-CC49, an anti-TAG-72 MAb, resulted in a statistically significant improvement in therapeutic efficacy when compared with 131I-CC49 alone. For example, treatment with 300 microCi of 131I-CC49 initially suppressed HT-29 tumor growth; however, that reduction in tumor growth was transient as evidenced by the emergence of additional tumor growth at later time points. In contrast, an 8-day treatment with IFN-gamma in combination with 300 microCi 131I-CC49 resulted in sustained suppression of HT-29 tumor growth. Thus, IFN-gamma in vivo can substantially increase the TAG-72 expression in human colon tumor xenografts which leads to an increased tumor localization of anti-TAG-72 MAbs and seems to be responsible for the enhanced antitumor effects when IFN-gamma was combined with 131I-CC49. The results provide further evidence for including a biological response modifier, such as IFN-gamma, which can increase the expression of specific tumor antigens (i.e., TAG-72 and CEA) subsequently leading to a dramatic improvement in the antitumor efficacy of a radionuclide-conjugated MAb.


Assuntos
Neoplasias do Colo/terapia , Imunotoxinas/uso terapêutico , Interferon gama/farmacologia , Radioisótopos do Iodo/uso terapêutico , Radioimunoterapia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/fisiologia , Antígeno Carcinoembrionário/fisiologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Terapia Combinada , Relação Dose-Resposta a Droga , Humanos , Imunotoxinas/metabolismo , Camundongos , Camundongos Nus , Proteínas Recombinantes , Transplante Heterólogo
20.
J Immunother (1991) ; 12(4): 231-41, 1992 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1477074

RESUMO

Human colorectal carcinoma cells that were treated in vitro with interleukin-6 (IL-6) expressed increased levels of carcinoembryonic antigen (CEA) and normal histocompatibility leukocyte antigen (HLA) class I on their cell surface. The IL-6 mediated increase of CEA expression on the surface of a moderately differentiated colon carcinoma cell line (WiDr) was time- and dose-dependent. A 5-day treatment of the WiDr cells with 100 U IL-6/ml increased the percentage of cells that expressed CEA from 29 to > 80% and enhanced the level of HLA class I expression. The increase in CEA expression as a result of IL-6 treatment was also observed using SDS-PAGE/Western blot analyses, and subsequent Northern blot analyses revealed concomitant increases in CEA-related mRNA transcripts. A comparison of the increases in CEA expression after IL-6, interferon-beta, and interferon-gamma on a nanomolar basis revealed that IL-6 was more potent than either of the interferons. Of 11 different human colorectal tumor cell lines that were treated with IL-6, CEA and/or HLA class I expression were increased in five. Thus, IL-6 can act directly on human colon carcinoma cells and selectively increase the expression of CEA and HLA class I antigens, which may provide some insight into the mechanisms involved in the ability of IL-6 to suppress in vivo tumor growth.


Assuntos
Antígenos de Neoplasias/biossíntese , Antígeno Carcinoembrionário/biossíntese , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/biossíntese , Interleucina-6/farmacologia , Proteínas de Neoplasias/biossíntese , Neoplasias Colorretais/patologia , Humanos , Interferon beta/farmacologia , Interferon gama/farmacologia , Receptores Imunológicos/análise , Receptores de Interleucina-6 , Proteínas Recombinantes/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos
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