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1.
Br J Cancer ; 110(11): 2756-64, 2014 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-24743708

RESUMO

BACKGROUND: Data characterising long-term survivors (LTS) with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. This analysis describes LTS using registHER observational study data. METHODS: A latent class modelling (LCM) approach was used to identify distinct homogenous patient groups (or classes) based on progression-free survival (PFS), overall survival, and complete response. Demographics, clinicopathologic factors, first-line treatment patterns, and clinical outcomes were described for each class. Class-associated factors were evaluated using logistic regression analysis. RESULTS: LCM identified two survivor groups labelled as LTS (n=244) and short-term survivors (STS; n=757). Baseline characteristics were similar between groups, although LTS were more likely to be white (83.6% vs 77.8%) with oestrogen receptor-positive (ER+) or progesterone receptor-positive (PgR+) disease (59.4% vs 50.9%). Median PFS in LTS was 37.2 (95% confidence interval (CI): 32.9-40.5) vs 7.3 months (95% CI: 6.8-8.0) in STS. Factors associated with long-term survival included ER+ or PgR+ disease, metastasis to node/local sites, first-line trastuzumab use, and first-line taxane use. CONCLUSIONS: Prognostic variables identified by LCM define a HER2-positive MBC patient profile and therapies that may be associated with more favourable long-term outcomes, enabling treatment selection appropriate to the patient's disease characteristics.


Assuntos
Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama Masculina/patologia , Neoplasias da Mama Masculina/terapia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Observacionais como Assunto , Modelos de Riscos Proporcionais , Sistema de Registros , Sobreviventes , Resultado do Tratamento , Adulto Jovem
2.
Breast Cancer Res Treat ; 115(1): 123-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18543100

RESUMO

BACKGROUND: There has been growing interest in providing clinical trial participants with study results yet only limited information exists regarding the process and impact of sharing results. We sought to evaluate patient perceptions of how results had been shared from a large randomized cooperative group trial, and the impact of learning results. PATIENTS AND METHODS: A subset of women who participated in NCCTG 9831 (A Phase III Trial of Adjuvant Chemotherapy with or without Trastuzumab for Women with HER2-positive Breast Cancer) were mailed surveys after the preliminary study results were released to the public and mailed to participants. RESULTS: One hundred and 67 of 228 surveys sent (73%) were returned; 61% reported receiving trastuzumab on study; 4% reported recurrent disease. Ninety-five percent of participants were glad they received results; 81% were satisfied with how results were shared; 23% were more anxious after learning the results. Sixty-nine percent correctly interpreted the results. Logistic regression revealed that satisfaction with the process of receiving results was associated with satisfaction with treatment (P = 0.04), and increased anxiety was associated with dissatisfaction with treatment (0.02), incorrect interpretation of results (0.04), and not having received trastuzumab (P < 0.0001). CONCLUSION: Sharing results directly with study participants is met with overwhelmingly favorable responses from patients, although some may not initially understand the findings. The potential for increased anxiety should be considered, and psychosocial support may be required by some. A plan to share results should be routinely and prospectively considered in the design of cancer clinical trials.


Assuntos
Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Ansiedade , Quimioterapia Adjuvante , Comunicação , Coleta de Dados , Humanos , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Satisfação do Paciente , Percepção , Recidiva , Análise de Regressão , Projetos de Pesquisa , Trastuzumab
3.
J Immunol Methods ; 248(1-2): 149-65, 2001 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11223076

RESUMO

INTRODUCTION: MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and Fab' mAbH22 (anti-CD64). STUDY DESIGN AND OBJECTIVES: This was a dose escalation study of intravenous MDX-H210 (1-70 mg/m(2)), preceded 24 h beforehand by subcutaneous IFNgamma (50 microg/m(2) to up-regulate FcgammaRI) administered three times a week for 3 weeks. We investigated the pharmacokinetic-pharmacodynamic relationships between MDX-H210 C(max) and AUC and (i) MDX-H210 binding to peripheral blood monocytes and neutrophils, (ii) the peak plasma G-CSF, IL-6, IL-8 and TNFalpha concentrations, and (iii) the observed clinical toxicity. RESULTS: 23 patients (19F:4M; median age 51.5; range 25-72 y) with advanced HER-2/neu positive cancers (19 breast, three prostate and one lung) were studied. Plasma MDX-H210 concentrations over time, circulating numbers of monocytes and neutrophils, percent saturation of monocyte and neutrophil FcgammaRI, and plasma concentrations over time of G-CSF, IL-6, IL-8 and TNFalpha were measured and clinical toxicity monitored. The E(max) pharmacodynamic model best fitted the relationship of MDX-H210 C(max) and the maximum percent saturation of both monocytes (E(max)=74.6; EC(50)=0.9 microg/ml) and neutrophils (E(max)=66.2; EC(50)=2.3 microg/ml) on the first day of treatment. On the last day of treatment, day 19, these parameters were E(max)=57.0% and EC(50)=0.46 microg/ml for monocytes and E(max)=61.9% and EC(50)=0.26 microg/ml for neutrophils. No positive relationship was defined between the log MDX-H210 C(max) and the log peak plasma IL-6, G-CSF, TNF or IL-8 concentrations on day 1. On day 19 these plasma cytokine concentrations were undetectable post MDX-H210 therapy. There was no consistent relationship between MDX-H210 C(max) and the observed clinical toxicities. CONCLUSIONS: These data suggest that MDX-H210 C(max) and AUC could be related by the E(max) model to maximum percent FcgammaRI saturation on circulating monocytes and neutrophils in the patients studied. After day 1, the post MDX-H210 therapy cytokine response attenuated over time, consistent with desensitization. We did not find a relationship between log MDX-H210 C(max) and peak plasma cytokine concentrations or clinical toxicities.


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Interferon gama/administração & dosagem , Neoplasias/terapia , Receptor ErbB-2/imunologia , Receptores de IgG/imunologia , Adulto , Idoso , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/fisiologia , Neutrófilos/fisiologia , Receptor ErbB-2/análise
4.
J Immunol Methods ; 248(1-2): 167-82, 2001 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11223077

RESUMO

Studies from our laboratory and others have established that both mononuclear phagocytes and neutrophils mediate very efficient cytotoxicity when targeted through Fc receptors using a suitable monoclonal or bispecific antibody (BsAb). Cross-linking an Fc receptor for IgG (FcgammaR) triggers multiple anti-tumor activities including superoxide generation, cytokine and enzyme release, phagocytosis and antibody-dependent cellular cytotoxicity (ADCC). In this report, using unfractionated leukocytes and two color flow cytometric analysis, we describe the phagocytic capacity of peripheral blood polymorphonuclear cells (PMN) and monocytes isolated from patients enrolled in a phase I clinical trial of MDX-H210 given in combination with IFNgamma. MDX-H210 is a BsAb targeting the myeloid trigger molecule FcgammaRI and the HER-2/neu proto-oncogene product overexpressed on a variety of adenocarcinomas. In this trial, cohorts of patients received escalating doses of MDX-H210 3 times per week for 3 weeks. Interferon-gamma (IFNgamma) was given 24 h prior to each BsAb infusion. Our results demonstrate that monocytes from these patients were inherently capable of phagocytosing the HER-2/neu positive SK-BR-3 cell line and that addition of MDX-H210 into the assay significantly enhanced the number of targets phagocytosed. Two days after administration of an immunologically active dose of MDX-H210 (10 mg/m2), monocytes from these patients were able to phagocytose greater amounts of target cell material, indicating that these cells remained armed with functionally sufficient BsAb for at least 48 h. PMN from these patients very efficiently mediated phagocytosis through FcgammaRI after being treated with IFNgamma, but not before. We conclude that phagocytosis is not only an efficient mechanism of myeloid cell-mediated cytotoxicity, but may also be a mechanism by which antigens from phagocytosed cells can enter a professional antigen presenting cell for processing and presentation.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Monócitos/imunologia , Neoplasias/terapia , Neutrófilos/imunologia , Fagocitose , Receptor ErbB-2/análise , Animais , Anticorpos Monoclonais Humanizados , Citotoxicidade Celular Dependente de Anticorpos , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Citometria de Fluxo , Humanos , Interferon gama/farmacologia , Camundongos , Neoplasias/imunologia , Proto-Oncogene Mas , Receptor ErbB-2/imunologia , Receptores de IgG/imunologia , Células Tumorais Cultivadas
5.
J Immunother ; 24(1): 79-87, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11211151

RESUMO

The goal of this study was to evaluate, in patients with prostate cancer, the toxicity profile and biologic activity of the bispecific antibody MDXH210, which has specificity for the non-ligand-binding site of the high-affinity immunoglobulin G receptor (Fc gamma RI) and the extracellular domain of the HER-2/neu proto-oncogene product. Patients with prostate cancer that expressed HER-2/neu were entered into a phase I dose-escalation trial of MDXH210. Patients received an intravenous infusion MDXH210 during a period of 2 h three times per week for 2 weeks and were monitored for toxicity. Pharmacokinetic and pharmacodynamic parameters were measured and included the biologic end points of monocyte-bound MDXH210, cytokine production, and clinical response. Seven patients were treated with MDXH210 doses ranging from 1 to 8 mg/m2. In general, MDXH210 was well tolerated, with only mild infusion-related malaise, fever, chills, and myalgias. No dose-limiting toxic effects were observed. Biologic effects included induction of low plasma concentrations of tumor necrosis factor-alpha and interleukin-6 observed immediately after MDXH210 infusion and 70% saturation of circulating monocyte-associated Fc gamma RI with MDXH210 at a dose level of 4 to 8 mg/m2. Five of six patients had stable prostate-specific antigen levels during the course of 40 days or more. Circulating plasma HER-2/neu levels decreased by 80% at days 12 and 29 (p = 0.03 and 0.06, respectively, by the Wilcoxon signed rank test). MDXH210 can be given safely to patients with HER-2/neu-positive prostate cancer in doses of at least 8 mg/m2. At the doses studied, biologic activity was demonstrated and characterized by binding of MDXH210 to circulating monocytes, release of monocyte-derived cytokines, a decrease in circulating HER-2/neu, and short-term stabilization of prostate-specific antigen levels.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Receptor ErbB-2/imunologia , Receptores de IgG/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Citocinas/sangue , Humanos , Imunização Passiva , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Projetos Piloto , Neoplasias da Próstata/metabolismo , Proto-Oncogene Mas , Receptor ErbB-2/biossíntese , Receptor ErbB-2/sangue , Receptores de IgG/biossíntese
6.
Methods Mol Med ; 39: 793-806, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-21340841

RESUMO

A large number of monoclonal antibodies (MAbs) to various tumor cell lines have been developed (1). However, MAbs have thus far had limited therapeutic impact in oncology, probably in part because many murine MAbs do not effectively recruit immune effector mechanisms, such as complement fixation and antibody-dependent cell-mediated cytotoxicity (ADCC) in humans. Additionally, although humanized MAbs are being developed, when used therapeutically their immunological effectiveness may be limited by high concentrations of nonspecific immunoglobulin (Ig) in patient serum. These nonspecific Ig will compete with conventional MAbs for binding to Type I Fc receptors (FcγRI) on immune effector cells, and may therefore limit conventional MAbs ability to recruit an immune response. Recently, however, clinical efficacy of a humanized MAb directed against HER-2/neu in patients with advanced breast cancer has been demonstrated (2-4). Preclinical data suggests that mechanistically this activity may be as a consequence of modulation of important biologic properties of the HER-2/neu receptor itself, as opposed to through an immunologic mechanism of tumor cell destruction.

7.
Semin Oncol ; 26(3 Suppl 8): 39-46, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10403473

RESUMO

Numerous clinical trials have demonstrated that the combination of paclitaxel and doxorubicin is extremely active in metastatic breast cancer. Overall response rates of 42% to 94% and complete response rates of 4% to 41% have been reported. However, several trials with the highest response rates were associated with the development of congestive heart failure (CHF) in approximately 20% of patients. These early findings resulted in reducing the maximum permitted cumulative dosages of doxorubicin in subsequent trials, with a corresponding decrease in cardiac toxicity being noted. Several subsequent series suggest that with cumulative dosing of 360 mg/m2 doxorubicin, the rate of CHF can be reduced to approximately 5%. A recently completed Eastern Cooperative Oncology Group phase III randomized trial comparing paclitaxel versus doxorubicin versus combination therapy with paclitaxel and doxorubicin noted an overall response rate of 33% and 34% in each single-agent arm, respectively, and a response rate of 46% with the combination therapy. There was an acceptable incidence of CHF. However, no difference in overall survival was noted with the combination therapy compared with the single-agent treatment. Losoxantrone, an anthrapyrazole in clinical development, has shown promising single-agent activity in metastatic breast cancer. An initial phase III randomized clinical trial comparing treatment with either paclitaxel alone versus losoxantrone and paclitaxel was recently completed. With no maximal cumulative dosage of losoxantrone incorporated into this trial design, an overall incidence of CHF of 4.9% was noted with combination therapy. Other hematologic and nonhematologic toxicities were overall acceptable with this new regimen as well. Additionally, preliminary analyses of clinical efficacy suggest that this new combination is promising therapy for the treatment of patients with metastatic breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Pirazolonas , Antraquinonas/administração & dosagem , Neoplasias da Mama/patologia , Doxorrubicina/administração & dosagem , Humanos , Metástase Neoplásica , Paclitaxel/administração & dosagem , Pirazóis/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Cancer ; 78(9): 1906-11, 1996 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-8909310

RESUMO

BACKGROUND: Based on previous data demonstrating a potentially synergistic interaction between tamoxifen and cisplatin in metastatic melanoma therapy, a Phase II study was performed to assess the activity of tamoxifen, etoposide, mitoxantrone, and cisplatin (TEMP) in patients with metastatic breast carcinoma. METHODS: Forty-six patients with metastatic breast carcinoma were treated with tamoxifen, 10 mg orally, twice a day for 28 days; etoposide, 100 mg/m2, on Days 1-3; mitoxantrone, 10 mg/m2, on Day 1; and cisplatin, 30 mg/m2, on Days 1 and 2. Forty-four patients (7 with bone only disease) were evaluable for response and toxicity after at least 1 cycle of therapy. All patients had previously received doxorubicin-containing regimens in either the adjuvant or metastatic setting. RESULTS: The overall objective response rate for the 37 patients with visceral and/ or soft tissue disease was 41% (95% confidence interval, 25-58%). The objective response rate among women previously treated with doxorubicin in the adjuvant setting was 56% (14 of 24). Only 1 of 13 patients with metastatic carcinoma who had failed doxorubicin responded. Five of seven patients with bone-only disease had subjective improvement of bone pain without worsening of bone scans. Approximately 59% of patients had Grade 3 or 4 neutropenia at some time in their therapy and 1 patient died of neuropenic sepsis. Logistic regression analysis (n = 37) revealed that response was not related to estrogen receptor (ER) status or to the presence of visceral metastases. CONCLUSIONS: TEMP appears to be an active regimen for patients with either ER positive (tamoxifen-resistant) or ER negative metastatic breast carcinoma that progresses after adjuvant doxorubicin therapy. Moreover, among patients who developed metastatic disease either during or < 12 months after adjuvant doxorubicin therapy, TEMP had a higher response rate than would have been predicted from previous studies. Although the mechanism remains to be elucidated, these results suggest a potentially synergistic role for tamoxifen in etoposide/cisplatin-based chemotherapy of breast carcinoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Tamoxifeno/administração & dosagem
9.
J Hematother ; 4(5): 471-5, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8581387

RESUMO

MDX-210 is a bispecific antibody (BsAb) that recognizes Fc gamma R1 on monocytes and macrophages and the cell surface product of the HER-2/neu oncogene, which is overexpressed on some breast and ovarian cancers. Clinical trials have demonstrated that treatment with MDX-210 is well tolerated and that MDX-210 is both immunologically and clinically active. Optimization of the dose and schedule of MDX-210 and development of combination treatments with cytokines that modulate immune effector cells will greatly enhance the efficacy of this novel BsAb construct for treatment of tumours that overexpress HER-2/neu. We envision that MDX-210 will be effective for treating patients with tumors that overexpress HER-2/neu, especially in the minimal disease setting.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Proteínas de Neoplasias/imunologia , Neoplasias Ovarianas/terapia , Receptor ErbB-2/imunologia , Receptores de IgG/imunologia , Anticorpos Anti-Idiotípicos/biossíntese , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Antineoplásicos/administração & dosagem , Anticorpos Antineoplásicos/efeitos adversos , Anticorpos Antineoplásicos/imunologia , Especificidade de Anticorpos , Citotoxicidade Celular Dependente de Anticorpos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Estudos de Coortes , Terapia Combinada , Citocinas/metabolismo , Esquema de Medicação , Feminino , Humanos , Hipotensão/induzido quimicamente , Imunização Passiva , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Receptores Fc/imunologia
10.
J Clin Oncol ; 13(9): 2281-92, 1995 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7545221

RESUMO

PURPOSE: MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210. PATIENTS AND METHODS: Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2. RESULTS: Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients. CONCLUSION: MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias da Mama/terapia , Expressão Gênica , Genes erbB-2 , Neoplasias Ovarianas/terapia , Receptor ErbB-2/imunologia , Receptores de IgG/imunologia , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Biopterinas/análogos & derivados , Biopterinas/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Estudos de Coortes , Feminino , Febre/etiologia , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Hipotensão/etiologia , Infusões Intravenosas , Interleucina-6/sangue , Pessoa de Meia-Idade , Neopterina , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Proto-Oncogene Mas , Receptor ErbB-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
J Virol ; 66(8): 5018-29, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1321284

RESUMO

The v-rel oncogene product from the avian reticuloendotheliosis virus strain T corresponds to a member of the Rel-related family of enhancer-binding proteins that includes both the mammalian 50- and 65-kDa subunits of the NF-kappa B transcription factor complex. However, in contrast to NF-kappa B, v-Rel has been shown to function as a dominant-negative repressor of kappa B-dependent transcription in many mature cell types. We now demonstrate that a highly conserved motif within the Rel homology domain of v-Rel containing a consensus protein kinase A phosphorylation site is required for DNA binding, transcriptional repression, and cellular transformation mediated by this oncoprotein. However, replacement of the serine phosphate acceptor within the protein kinase A site with an alanine did not alter any of these functions of v-Rel, suggesting that phosphorylation at this site is not central to the regulation of this oncogene product. Rather, the inactive mutations appear to identify a functional domain within v-Rel required for these various biological activities. It is notable that these same mutations do not impair the ability of v-Rel to heterodimerize with the 50-kDa subunit of NF-kappa B, suggesting that v-Rel-mediated transcriptional repression likely involves direct nuclear blockade of the kappa B enhancer rather than indirect alterations in the composition of preformed cytoplasmic NF-kappa B complexes. Paradoxically, when introduced into undifferentiated F9 cells, v-Rel functions as a kappa B-specific transcriptional activator rather than as a dominant-negative repressor. These stimulatory effects of v-Rel require both the conserved protein kinase A phosphorylation site and additional unique C-terminal sequences not needed for v-Rel-mediated repression in mature cells. Retinoic acid-induced differentiation of these F9 cells restores the repressor function of v-Rel. These opposing biological actions of v-Rel occurring in cells at distinct stages of differentiation may have important implications for the mechanism of v-Rel-mediated transformation occurring in avian splenocytes.


Assuntos
Transformação Celular Neoplásica , Regulação Viral da Expressão Gênica , Oncogenes , Vírus da Reticuloendoteliose/genética , Proteínas Oncogênicas de Retroviridae/genética , Ativação Transcricional , Sequência de Aminoácidos , Animais , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Cloranfenicol O-Acetiltransferase/genética , Cloranfenicol O-Acetiltransferase/metabolismo , Vetores Genéticos , Dados de Sequência Molecular , NF-kappa B/metabolismo , Oligodesoxirribonucleotídeos , Proteínas Oncogênicas v-rel , Plasmídeos , Biossíntese de Proteínas , Proteínas Tirosina Quinases/genética , Homologia de Sequência do Ácido Nucleico , TATA Box , Teratoma , Transcrição Gênica , Transfecção
12.
J Clin Invest ; 90(1): 121-9, 1992 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1634604

RESUMO

The nuclear factor (NF)-kappa B transcription factor system is composed of at least four inducible nucleoprotein adducts termed p50, p55 (NF-kappa B p50), p75 (NF-kappa B p65), and p85 (c-Rel). These proteins are expressed in the nuclei of activated T cells in a distinctly biphasic fashion, with p55 and p75 induction occurring within minutes whereas the induction of p50 and p85 occurs after several hours. In contrast, p50 and p55 are constitutively expressed in the nuclei of U937 and THP-1 monocytic cells. However, cellular activation is required for the nuclear expression of p75 in these cells. Additionally, activation of monocytic cells does not result in a significant induction of p85. Tumor necrosis factor alpha induces the nuclear expression of p55 and p75 in these monocytic cells within 20 min, presumably reflecting the liberation of these proteins from I kappa B. In contrast, phorbol myristate acetate (PMA) induces the expression of these proteins with delayed kinetics, raising the possibility that PMA is incapable of mediating the efficient release of p55 and p75 from I kappa B in these cells. These findings highlight important differences in the regulation of these proteins in monocytic cells versus T cells and suggest that the induced expression of NF-kappa B p65 in monocytes may play a central role in the activation of HIV-1 gene expression.


Assuntos
Núcleo Celular/química , NF-kappa B/análise , Proteínas Proto-Oncogênicas/análise , Sequência de Bases , Linhagem Celular , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Repetição Terminal Longa de HIV , Humanos , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-rel , Acetato de Tetradecanoilforbol/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
13.
Adv Perit Dial ; 8: 55-8, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1361852

RESUMO

Urea kinetics have been used to measure adequacy of hemodialysis. The role of urea kinetics in CAPD has not been clearly established. Using urea kinetics, we studied 71 hemodialysis and 71 CAPD patients. Age was 53 +/- 12 and 45.8 +/- 12 respectively. Urea kinetics in hemodialysis were studied in the standard manner. CAPD patients collected 24 hr, dialysate fluid to measure urea, creatinine, glucose and protein. Urine was collected for 24 hr. to measure urea and creatinine. Protein catabolic rate (pcr) was calculated from the total amount of urea cleared in 24 h. Both groups of patients had similar body weight. Kt/V in CAPD (0.65 +/- 0.1) was at a level considered underdialysis for hemodialysis. In both groups, pcr increased as Kt/V increased. However, CAPD patients had levels of pcr higher than hemodialysis patients at the same level of Kt/V. BUN, serum albumin and serum potassium were significantly lower in CAPD patients. Patients who dialyze more, eat more. Differences in protein intake may be due to a more liberal diet in CAPD, patient selection, removal of middle molecules, or better control of the acidosis.


Assuntos
Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua , Diálise Renal , Ureia/farmacocinética , Adulto , Nitrogênio da Ureia Sanguínea , Soluções para Diálise/análise , Proteínas Alimentares/administração & dosagem , Feminino , Humanos , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Ureia/análise
14.
J Virol ; 65(1): 405-14, 1991 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-1985205

RESUMO

The Rex protein of the human T-cell leukemia virus type II (HTLV-II), Rex-II, plays a central role in regulating the expression of the structural genes of this retrovirus. Rex-II acts posttranscriptionally by inducing the cytoplasmic expression of the incompletely spliced viral mRNAs that encode the Gag and Env structural proteins and the enzymes derived from the pol gene. We now define a 295-nucleotide cis-acting regulatory element within the 3' long terminal repeat of HTLV-II that is required for the effects of Rex-II. This Rex-II response element (RexIIRE) corresponds to a predicted, highly stable RNA secondary structure and functions when present in the sense but not in the antisense orientation. The RexIIRE confers responsiveness not only to Rex-II but also to the Rex protein of HTLV-I. Deletion and substitution mutagenesis of the RexIIRE permitted identification of a small subregion within the larger element critically required for Rex-II responsiveness and further suggested that the structurally distinct RexIIREs generated from the 5' and 3' long terminal repeats of HTLV-II may differentially regulate the cytoplasmic expression of unspliced gag-pol and singly spliced env mRNAs. While the Rev protein of human immunodeficiency virus type 1 fails to function via the RexIIRE, the Rex-II protein, like Rex-I, can functionally replace the Rev protein of human immunodeficiency virus type 1 via its interaction with the Rev response element (RevRE).


Assuntos
Regulação Viral da Expressão Gênica , Produtos do Gene rex/metabolismo , Genes Virais , Vírus Linfotrópico T Tipo 2 Humano/genética , RNA Mensageiro/genética , Proteínas Estruturais Virais/genética , Animais , Sequência de Bases , Linhagem Celular , Deleção Cromossômica , Genes pX , Vetores Genéticos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Conformação de Ácido Nucleico , Processamento Pós-Transcricional do RNA , Splicing de RNA , Sequências Repetitivas de Ácido Nucleico , Mapeamento por Restrição
15.
Adv Perit Dial ; 7: 47-50, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1680455

RESUMO

Adequacy of CAPD has not been established. The recommendation is a Kt/V (K, total urea clearance in ml/min; t. time in minutes on dialysis; and V, total body water which is the volume of distribution of urea) greater than 1.5/week and/or a creatinine clearance (residual + dialysis) greater than 40 l/week/1.73 m2. We followed 20 CAPD patients for 38.6 +/- 28 mo. We measured blood urea nitrogen, serum creatinine, body weight, residual renal function (Kr), normalized protein catabolic rate (NPCR), Kt/V/week and creatinine clearance (CC) l/w/1.73 m2. We obtained the following values: B Wt 72 +/- 16 kg, BUN 56 +/- 13 mg/dl, s. Cr. 12.6 +/- 5 mg/dl, Kr 0.6 +/- 1 ml/min, NPCR 0.84 +/- 0.3 g/kg/day, Kt/V/week 1.8 +/- 0.3 and CC 50.4 +/- 10 l/w/1.73 m2. Patients dialyzed with a wide range of prescription. There was a good correlation between Kt/V and CC. There was no correlation between the dialysis prescription changes in weight and biochemical determinations. There was a direct correlation between Kt/V and NPCR: patients who were dialyzed more eat more. Of the 20 patients, 10 had 24 hospitalizations, and of these were 12 due to peritonitis. Dialysis prescription and biochemical findings of these patients did not differ significantly from nonhospitalized patients. Larger prospective studies are necessary to determine the adequate range of CAPD prescription and its relationship to morbidity and mortality.


Assuntos
Diálise Peritoneal Ambulatorial Contínua , Adulto , Nitrogênio da Ureia Sanguínea , Creatinina/metabolismo , Feminino , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal Ambulatorial Contínua/métodos , Ureia/metabolismo
16.
Cancer ; 66(3): 515-21, 1990 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-2114212

RESUMO

Four patients who underwent treatment with high-dose chemotherapy (HDC) and autologous bone marrow transplantation (ABMT) and in whom posttreatment deficiencies of Factor XII and protein C subsequently developed are reported. Factor VII or Factor X deficiencies also developed in several of these patients. Three of these patients experienced chemotherapy-related cardiac, hepatic, or pulmonary toxicity. It is believed by many that endothelial cell injury may be the underlying lesion responsible for these various organ system toxicities seen in the setting of ABMT, although direct evidence of this is lacking. It is proposed that the factor deficiencies described in this report may be an additional consequence of endothelial cell injury or dysfunction. These coagulation factor deficiencies may therefore serve as both a marker to follow these organ system toxicities with and as a useful tool to better study and understand the mechanisms underlying these events. Additionally, deficiencies of either Factor VII or Factor X developed in several patients that were of a sufficient magnitude such that factor replacement therapy would be indicated before any invasive procedures or in the event of significant hemorrhage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Neoplasias da Mama/sangue , Deficiência do Fator VII/etiologia , Deficiência do Fator XII/etiologia , Melanoma/sangue , Deficiência de Proteína C , Adolescente , Adulto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Terapia Combinada , Fator VIII/metabolismo , Deficiência do Fator X/etiologia , Deficiência do Fator XI/etiologia , Feminino , Humanos , Melanoma/tratamento farmacológico , Melanoma/cirurgia
19.
Am J Psychiatry ; 141(4): 530-3, 1984 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-6703131

RESUMO

The authors present a collaborative treatment model designed to help the closely merged, troubled lesbian relationship. Therapeutic techniques focus on change in territorial, temporal, monetary, cognitive, emotional, and environmental space. A case example illustrates the interventions, which include individual and conjoint work, collaboration between therapists, education, bibliotherapy, referral to gay community resources, and specific suggestions for behavior change. The therapeutic goal is to restore intimacy to the relationship by offering each partner increased distance, personal space, and individual autonomy.


Assuntos
Homossexualidade , Relações Interpessoais , Psicoterapia/métodos , Adaptação Psicológica , Assertividade , Terapia Comportamental , Biblioterapia , Feminino , Humanos , Libido , Estilo de Vida , Amor , Pessoa de Meia-Idade , Espaço Pessoal , Psicoterapia Múltipla , Papel (figurativo) , Autoimagem , Territorialidade
20.
Am J Surg ; 130(2): 251-8, 1975 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-168792

RESUMO

Five hundred consecutive cases of breast carcinoma were studied to determine the incidence of multicentric lesions in the resected specimens. When residual tumor in juxtaposition to the primary tumor or biopsy cavity is excluded, 41.6 per cent of specimens exhibited multicentric foci of tumor; 31 per cent of such foci were in sectors or quadrants remote from the primary tumor. In more than half of these cases the lymph nodes were uninvolved and cure rate would have been maximal had these multicentric tumor foci been removed. These findings confirm previous similar studies and we consider tylectomy an inappropriate mode of therapy for breast cancer.


Assuntos
Adenocarcinoma/cirurgia , Neoplasias da Mama/cirurgia , Carcinoma in Situ/cirurgia , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma de Células Escamosas/cirurgia , Carcinoma/cirurgia , Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Carcinoma/patologia , Carcinoma in Situ/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Metástase Linfática , Mastectomia , Métodos , Mamilos/patologia , Mamilos/cirurgia
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