RESUMO
A central feature of tumor metastasis is the migration of malignant cells through interstitial tissues and vascular structures as they spread throughout the body. Various components of the extracellular matrix and of basement membranes, consisting of genetically distinct collagens, proteoglycans, and noncollagenous glycoproteins, are known to modulate certain aspects of cell behavior, including cell movement. Serum spreading factor is a glycoprotein component of human serum that is also found in interstitial tissues. Two native forms are seen in human serum, a Mr 65,000 and a Mr 75,000 component. Spreading factor promotes substratum attachment and spreading of diverse cell types, including epithelial and fibroblastic cells, and will affect the growth rate and differentiation of cells in serum-free culture media. Serum spreading factor was shown to promote the directed migration of the following tumor cell lines in modified Boyden chamber assays: murine melanoma K-1735 (clones M2, M4, and 16); human breast carcinoma MCF-7; and human fibrosarcoma HT-1080. The stimulation of movement occurred over a concentration range of 0.5 to 50 micrograms of serum spreading factor per ml with a maximum response between 5 and 10 micrograms/ml. The maximal response varied with the cell line and ranged from 5- to 50-fold greater migration than control. A monoclonal antibody to spreading factor, previously shown to inhibit the attachment and spreading-promoting activity, abrogated this migration response. Experiments using filters that were precoated with spreading factor indicated that cells could migrate on an insolubilized layer of this protein by haptotaxis. Tumor cell migration to spreading factor in vitro suggests a possible role for this protein in the phenotypic behavior of metastatic cells.
Assuntos
Movimento Celular/efeitos dos fármacos , Glicoproteínas/farmacologia , Neoplasias/patologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular , Feminino , Fibronectinas/farmacologia , Fibrossarcoma/patologia , Glicoproteínas/análise , Glicoproteínas/metabolismo , Granulócitos/citologia , Humanos , Laminina/farmacologia , Melanoma/patologia , Camundongos , VitronectinaRESUMO
This study assesses the ability of a blood donor cholesterol screening program to enhance awareness of cholesterol levels among screenees and to promote lifestyle changes and physician follow-up. Beginning in November 1990, all blood donors at the Minneapolis Veterans Affairs Medical Center were offered free cholesterol screening. Each screenee also received educational materials and brief counseling from a nurse. Two weeks after donation, screenees received a postcard with their cholesterol level and information regarding recommended follow-up. Baseline information for all screenees was obtained at the time of donation through a self-administered questionnaire. Follow-up data were collected through structured telephone interviews. During the program's first four months, 1,039 donors (33%) requested cholesterol screening. At baseline, 82.6% of screenees had at least one risk factor for coronary heart disease, and 37% had two or more risk factors. More than one third were unaware of their cholesterol levels. At follow-up, more than 95% indicated that they were aware of their cholesterol levels, and 90% of those with high cholesterol levels had followed up with their physician or made dietary or other lifestyle changes. We conclude that a cholesterol screening and minimal intervention program for blood donors enhances awareness of cholesterol levels and encourages dietary or other lifestyle changes.
Assuntos
Doadores de Sangue , Colesterol/sangue , Doença das Coronárias/etiologia , Programas de Rastreamento , Feminino , Humanos , Masculino , Fatores de Risco , Autoadministração , Inquéritos e QuestionáriosRESUMO
Fibrinogen Richfield exemplifies a dysfibrinogen associated with a life-long thrombotic tendency. The evaluation of this novel case indicates that, like similar thrombotic dysfibrinogenemias, the abnormal protein polymerizes abnormally and demonstrates impaired clot dissolution. A survey of other cases of dysfibrinogenemia indicates that the relatively common abnormalities of Fibrinopeptide A release are generally asymptomatic or associated with bleeding, polymerization abnormalities are likely to be asymptomatic or associated with thrombosis (or occasionally bleeding), and complex abnormalities or additional, independent hemostatic defects are rather common. Thrombin and Reptilase clotting times are not helpful in distinguishing between the subsets, but clinical history, fibrinopeptide release, and polymerization studies may be useful. Abnormalities of fibrinogen function tend to correlate with changes in molecular domains related to binding and hydrolysis.
Assuntos
Afibrinogenemia/sangue , Trombose/sangue , Afibrinogenemia/genética , Coagulação Sanguínea , Fibrina/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinolisina/metabolismo , Humanos , Masculino , Linhagem , Plasminogênio/metabolismo , Polímeros , Tempo de Trombina , Trombose/genética , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
The migration of tumour cells through basement membranes and extracellular matrices is an integral component of tumour invasion and metastasis. Laminin (LMN) and fibronectin (FN) at 1-100 micrograms/ml promote the directed migration of metastatic murine melanoma cells 40-70-fold greater than controls in modified Boyden chambers. Antibodies abrogated the migration of cells in response to the respective protein. Preincubation of melanoma cells with plasma FN had no effect on subsequent migration to LMN or FN. The migration of these cells was largely related to substratum-attached molecules and increasing adhesion gradients of cells; this has been termed haptotaxis. Peptide fragments of both FN and LMN were isolated by affinity chromatography with monoclonal antibodies, heparin or other constituents. FN has two unique domains, 80-125 K and 66 K, which promote the adhesion of tumour cells, whereas only one appeared to be responsible for promoting migration. Peptides of LMN, isolated with heparin and monoclonal antibody, define a cell migration-promoting activity within the 200 K chains of LMN. Serum spreading factor and epinectin, the latter an adhesion molecule derived from squamous epithelial tumour cells, are also capable of promoting the migration of malignant cells. Thus, directed migration of metastatic tumour cells may be promoted with peptide fragments of adhesion molecules and blocked with the respective antibody.
Assuntos
Movimento Celular , Fibronectinas/fisiologia , Laminina/fisiologia , Metástase Neoplásica , Animais , Membrana Basal/fisiologia , Adesão Celular , Células Cultivadas , Quimiotaxia , Matriz Extracelular/fisiologia , Melanoma/patologia , Camundongos , Fragmentos de Peptídeos/fisiologia , Relação Estrutura-AtividadeRESUMO
Metastasizing tumor cells must traverse diverse extracellular matrices during dissemination. Extracellular matrices consist of two basic types, interstitial stroma and basement membranes. Extracellular matrices are chemically complex structures that interact with cell surfaces by a number of mechanisms. There has been a great deal of effort in recent years to understand the molecular nature of extracellular matrices, especially as it relates to the adhesion of normal and malignant cell types. Adhesive noncollagenous glycoproteins, such as laminin and fibronectin, serve pivotal roles in basement membrane and stromal matrices, respectively. These proteins participate in establishing the architecture of extracellular matrices as well as in attaching to the surface of cells and affecting cellular phenotype. This phenotypic effect ranges from adhesion and motility to growth and differentiation. Changes in adhesive characteristics and motility of cells have long been suspected to play a role in mediating the spread of malignant neoplasms. This article is designed to review extracellular matrix constituents that are currently known that can mediate the adhesion and motility of malignant neoplasms. The adhesion of normal and malignant cells to matrices is a complex process mediated by several distinct mechanisms which are initially manifested by changes in cytoskeletal architecture. The topic of normal and malignant cell adhesion to matrices will also be discussed in this regard, since any explanation of tumor cell migration must account for the complex dynamic interactions of the cell surface with the substratum as well as with the cytoskeleton. Finally, current efforts designed to understand the molecular nature of tumor cell:matrix interactions that contribute to metastatic behavior will also be discussed. The rationale behind these studies is that selective inhibition of specific tumor:extracellular matrix interactions can provide an avenue for therapeutic intervention of metastatic cancer.
Assuntos
Movimento Celular , Fibronectinas/fisiologia , Laminina/fisiologia , Metástase Neoplásica/patologia , Neoplasias/patologia , Animais , Adesão Celular , Quimiotaxia , Colágeno/fisiologia , Glicosaminoglicanos/fisiologia , Humanos , Substâncias Macromoleculares , Peso Molecular , Conformação Proteica , Proteoglicanas/fisiologiaRESUMO
OBJECTIVE: The prevalence of psychiatric problems and substance abuse is high in the veteran population with hepatitis C. The purpose of this study was to retrospectively analyze the effect of preexisting psychiatric conditions in veteran patients undergoing treatment with interferon a-2b (IFN-alpha) with respect to adverse events, compliance, and treatment response. METHODS: Thirty-three veterans with chronic hepatitis C were treated with IFN-alpha (5 million units three times weekly) for 6 months, followed by a tapering dose for an additional 6 months. All patients fulfilled standard criteria for treatment eligibility. Psychiatric diagnoses, adverse events, and virological and biochemical responses to therapy were determined. RESULTS: Nineteen of 33 (58%) patients with hepatitis C had documented psychiatric conditions before starting IFN-alpha therapy. Of the patients with preexisting psychiatric diagnoses, 13/19 (68%) developed major adverse events requiring intervention or discontinuation of therapy. In contrast, 4/14 (29%) patients without psychiatric diagnoses developed major adverse events (p = 0.024) In the psychiatric group, 6/19 (32%) developed major neuropsychiatric side effects compared with 2/14 patients (14%) in the nonpsychiatric group (p = 0.25). Patients with and without psychiatric diagnoses had equivalent biochemical and virological responses to therapy. Overall, only 2/33 (6%) patients had a sustained virological response. CONCLUSIONS: Veterans with chronic hepatitis C and psychiatric diagnoses experienced a significantly greater number of major adverse events during treatment with IFN-alpha. Veteran patients with hepatitis C should be carefully screened for psychiatric conditions and may require more intensive monitoring during IFN-alpha therapy.
Assuntos
Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Transtornos Psicóticos/complicações , Adulto , Feminino , Seguimentos , Hepatite C Crônica/diagnóstico , Humanos , Interferon alfa-2 , Pessoa de Meia-Idade , Probabilidade , Transtornos Psicóticos/diagnóstico , Proteínas Recombinantes , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , VeteranosRESUMO
The data show that in chronic lymphocytic leukemia (CLL) there are elevated numbers of peripheral blood lymphocytes (PBL) capable of rosette formation (complement-rosetting lymphocytes, CRL) with bacteria (B)-antibody-(A)-complement (C) (BAC) complexes. In most of the CLL patients studied, large percentages of CRL were impaired in their ability to undergo BAC-C3R cap formation compared to normal donors. The degree of impairment varied from one patient to the next. A consideration of clinical information suggested that the variation was related to the clinical response of patients to chemotherapy. Four categories of CLL patients could be identified on the basis of clinical data: (1) patients never received therapy for CLL; (2) those whose clinical history indicated a failure to respond to ongoing chemotherapy; (3) patients who had received successful prior chemotherapy and who were asymptomatic or stable and were receiving no therapy at the time of study; and (4) those who were undergoing therapy at the time of study and who subsequently became stable or asymptomatic and were removed from therapy. The first two categories of patients failed to show significant BAC-C3R capping, whereas the last two were able to form C3R caps on significant percentages of CRL. No direct relationship could be discerned between C3R capping and currently accepted classifications on stages (Rai) of CLL. These results suggest that monitoring the percentages of BAC-C3R cap-forming CRL may be useful in determining the success of chemotherapy of CLL patients. The microtubule-disrupting agent colchicine enhanced BAC-C3R capping in all CLL patients to normal levels, whereas the microfilament-disrupting agents cytochalasin B(CB) had no effect on CLL RBL C3R capping. CB totally abolished C3R capping of CRL from normal donors. These results suggest that abnormalities exist in both cytoskeletal and contractile systems of CR from CLL peripheral blood.