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Biomedical subjects

R Sawaya

Publications and source records attributed to R Sawaya.

At least 109 records · Page 6Linked to original sources
PubMed1994

Elevated levels of plasminogen activators in the pathogenesis of delayed radiation damage in rat cervical spinal cord in vivo.

The pathophysiology of the cellular basis of radiation-induced demyelination and white-matter necrosis of the central nervous system (CNS) is poorly understood. Preliminary data suggest that tissue damage is partly mediated through changes in the proteolytic enzymes. In this study, we irradiated rat cervical spinal cords with single doses of 24 Gy of 18 MV photons or 20 MeV electrons and measured the levels of plasminogen activators at days 2, 7, 30, 60, 90, 120, 130 and 145 after irradiation, using appropriate controls at each time. Fibrin zymography revealed fibrinolytic bands representing molecular weights of 68,000 and 48,000 in controls and irradiated samples; these bands increased significantly at days 120, 130 and 145 after irradiation. Inhibition of these enzymatic bands with specific antibodies against tissue-type plasminogen activator (tPA) and amiloride, an inhibitor for urokinase plasminogen activator (uPA), confirmed that these bands were tPA and uPA. Enzymatic levels quantified by densitometry showed a twofold elevation in the levels of tPA and more than a tenfold increase in uPA after 120 days' irradiation. Activity of uPA was increased threefold by day 2 and increased steadily with time compared to nonirradiated control samples. Enzyme-linked immunosorbent assay (ELISA) also showed a threefold increase in the tPA content in the extracts of irradiated rat cervical spinal cords at days 120, 130 and 145. This study adds additional information to the proposed role of plasminogen activators in the pathogenic pathways of radiation damage in the CNS.

Animals↗
PubMed1993

Decreased levels of glia-derived nexin/protease nexin I in irradiated rat spinal cord in vivo.

The pathophysiology of the cellular basis of radiation induced demyelination and white matter necrosis of the Central Nervous System (CNS) is poorly understood. There have been no previous studies that have shown the effect of irradiation on glia-derived nexin. In this study, rats were given cervical spinal cord irradiation, and glial derived nexin or protease nexin I (GDN/PNI) was measured on days 2, 7, 30, 60, 120, 130, and 145 after irradiation. The level of GDN/PNI significantly decreased after irradiation compared to levels in control spinal cord, and there was no detectable levels of GDN/PNI by the time paralysis developed. This study adds considerable weight to the proposal that GDN/PNI has an important role in the pathogenesis of CNS radiation damage.

Amyloid beta-Protein Precursor↗
PubMed1993

Modulation of in vitro invasion of human glioblastoma cells by urokinase-type plasminogen activator receptor antibody.

Four human glioblastoma cell lines (U251, UWR1, UWR2, and UWR3) were tested for the expression of the cell surface receptor for urokinase-type plasminogen activator (uPA). To our knowledge there have been no previous reports about the uPA receptors (uPARs) in glioblastoma cell lines. All four glioblastoma cell lines we tested were found to bind recombinant Pro-uPA saturably and reversibly. Scatchard analysis of radioligand binding with acid-pretreated cells showed the presence of a single population of high-affinity uPARs on glioblastoma cells. Northern blot analysis confirmed that glioblastoma cells like other human cell lines express a 1.4-kilobase uPAR mRNA and 2.4-kilobase uPA mRNA. The significance of the uPAR in the invasive potential of the cells was examined by incubating uPAR antibody in an in vitro invasion assay. The anti-uPAR monoclonal antibody blocked the invasion effectively in a Matrigel assay, in which inhibition of invasion ranged between 20 and 57% for the cells studied. These data suggest that the uPARs contribute significantly to the invasive capacity of the cells, possibly by facilitating uPA activity.

Antibodies, Monoclonal↗
PubMed1993

Elevated levels of M(r) 92,000 type IV collagenase in human brain tumors.

Local invasive growth is one of the key features of primary malignant brain tumors accompanied by remodeling of the vasculature and destruction of normal brain tissue. Tissue invasiveness is an essential biological function used by a tumor to overcome the various barriers to its progression. The expression of metalloproteases has been shown to play a critical role in the invasive process in a number of tumors; however, their expression in human brain tumors has not been previously reported. In this study we showed metalloprotease activities at M(r) 240,000, 123,000, 92,000, 72,000, and 67,000 in brain tumor extracts. These enzyme activities were inhibited by EDTA, an inhibitor of metalloproteases. Significant increases in levels of protease bands at M(r) 92,000, 123,000, and 240,000 were observed in glioblastoma and metastatic lung tumors. Enzymatic inhibition and Western blotting with M(r) 92,000 type IV collagenase antibody confirmed the presence of M(r) 92,000 type IV collagenase in all samples. Quantitative analysis by densitometry showed 8-10-fold and 6-8-fold increases in M(r) 92,000 type IV collagenase activity in glioblastoma and metastatic lung carcinoma samples, respectively, when compared with normal brain, meningioma, astrocytoma, metastatic colon, and breast carcinoma samples. These findings provide evidence for elevated levels of metalloproteases in glioblastomas and suggest a therapeutic target for minimizing the invasive propensity of gliomas using protease inhibitors.

Antibodies↗
PubMed1993

Increased levels of plasminogen activator inhibitor-1 (PAI-1) in human brain tumors.

Considerable interest in the roles of serine proteases and serine protease inhibitors (serpins) in regulating physiologic and pathologic tissue remodeling has led to studies that indicate their critical participation in development and diseases of the brain. Plasminogen activator inhibitor-1 (PAI-1) is the most significant regulator of fibrinolysis in plasma, but little is known of the levels or activities of this important serpin in normal brain and brain tumors. For this reason, we estimated qualitative and quantitative levels of PAI-1 in normal human brain and various brain tumors. Western-blot results indicated that a 51 kDa band recognized with polyclonal anti-PAI-1 was more prominently in metastatic and glioblastoma than in meningiomas and low-grade gliomas; normal human brain lacked any detectable band. Reverse zymography also showed high levels of PAI-1 in malignant brain tumors. The complex formation with 125I-urokinase demonstrated that PAI-1 complex levels were increased in metastatic and glioblastoma when compared with low-grade gliomas and meningiomas. Since PAI-1 acts as a modulator of fibrinolysis, a better understanding of the balance between serine proteases and PAI-1 is likely to enhance our knowledge of brain tumor biology.

Blotting, Western↗
PubMed1993

Surgical treatment of multiple brain metastases.

The authors conducted a retrospective review of the charts of 56 patients who underwent resection for multiple brain metastases. Of these, 30 had one or more lesions left unresected (Group A) and 26 underwent resection of all lesions (Group B). Twenty-six other patients with a single metastasis who underwent resection (Group C) were selected to match Group B by type of primary tumor, time from first diagnosis of cancer to diagnosis of brain metastases, and presence or absence of systemic cancer at the time of surgery. Statistical analysis indicated that Groups A and B were also homogeneous for these prognostic indicators. Median survival duration was 6 months for Group A, 14 months for Group B, and 14 months for Group C. There was a statistically significant difference in survival time between Groups A and B (p = 0.003) and Groups A and C (p = 0.012) but not between Groups B and C (p > 0.5). Brain metastasis recurred in 31% of patients in Group B and in 35% of those in Group C; this difference was not significant (p > 0.5). Symptoms improved after surgery in 65% of patients in Group A, 83% in Group B, and 84% in Group C. Symptoms worsened in 13% of patients in Group A, 6% in Group B, and 0% in Group C. Groups A, B, and C had complication rates per craniotomy of 8%, 9%, and 8%, and 30-day mortality rates of 3%, 4%, and 0%, respectively. Guidelines for management of patients with multiple brain metastases are discussed. The authors conclude that surgical removal of all lesions in selected patients with multiple brain metastases results in significantly increased survival time and gives a prognosis similar to that of patients undergoing surgery for a single metastasis.

Adult↗
PubMed1993

Minimally invasive brain surgery.

Minimally invasive brain surgery refers to technological advances refining surgical access that have enabled neurosurgeons to reduce the morbidity and improve the accuracy and quality of neurosurgical procedures. These advances include computer-assisted stereotaxis, intraoperative ultrasound, brain mapping and neuroendoscopy. Computer-assisted stereotaxis includes not only smaller and accurate craniotomies but precision radiotherapy with radiosurgery and interstitial brachytherapy.

Brain Diseases↗
PubMed1992

Postoperative venous thromboembolism and brain tumors: Part III. Biochemical profile.

The plasminogen activator activity of 31 human brain tumor samples was assessed and the results correlated with clinical parameters and the postoperative occurrence of venous thrombosis. A significant negative correlation was found between plasminogen activator activity and venous thrombosis (P = 0.02), while positive correlations were observed between plasminogen activator activity and peritumoral brain edema (P = 0.03) and alpha 2 antiplasmin measured in the systemic circulation (P = 0.01). Tissue plasminogen activator was found in higher concentrations in meningioma tissue but did not correlate significantly with the occurrence of venous thrombosis. The results of this study suggest a local enzymatic degradation effect of plasminogen activator on thrombogenic substances present in the brain tumor and/or its environment.

Blood Coagulation Tests↗
PubMed1992

Postoperative venous thromboembolism and brain tumors: Part I. Clinical profile.

Forty-six patients who underwent surgery for brain tumors were studied prospectively with 125I labeled Fibrinogen leg scans to detect postoperative venous thrombosis. The incidence of thrombosis was 72% for meningioma patients, 60% for glioblastoma patients, and 20% for brain metastasis patients. Correlation between the occurrence of venous thrombosis and the various clinical factors thought to be responsible for the high incidence of thrombosis generally failed to show statistical significance. This finding, along with the marked variation in the incidence of venous thrombosis between the different brain tumor groups, strongly suggests that biological factors play a more important role than clinical factors in determining which brain tumor patient will suffer a postoperative thrombotic event.

Brain Neoplasms↗
PubMed1992

Postoperative venous thromboembolism and brain tumors: Part II. Hemostatic profile.

Preoperative hemostatic data were obtained on 42 brain tumor patients and correlated with the subsequent occurrence of venous thrombosis detected with 125I-labeled fibrinogen leg scans. The occurrence of thrombosis correlated significantly with an increased prothrombin time, plasminogen, and total fibrinolytic activity and a decreased fibrinogen level. This overall trend in the group of patients with postoperative thrombosis indicates that the hemostatic disorder noted in brain tumor patients is most closely related to a subclinical form of chronic disseminated intravascular coagulation syndrome. Differences in hemostatic parameters seen with the various types of brain tumors suggest that biological factors specific to each tumor are likely responsible for the described hemostatic disorder and support the need for further research directed at the tumor tissue level.

Blood Coagulation Tests↗
PubMed1992

Intracranial osteolytic malignant meningiomas appearing as extracranial soft-tissue masses.

Malignancy is rare in intracranial meningiomas. Although the topic is widely discussed, there is little agreement in the literature as to the histological and radiological features that warrant the diagnosis of malignant meningioma. Three patients are described who had soft-tissue masses and underlying osteolytic lesions on computed tomography. All three patients also had a large intracranial component that proved to be a malignant meningioma. Rarely do meningiomas have all three of these features. We propose that a meningioma causing osteolysis and soft-tissue extension should be considered malignant until proven otherwise.

Aged↗
PubMed1991

Plasma fibrinolytic profile in patients with brain tumors.

Changes in the fibrinolytic and coagulation values measured preoperatively in brain tumor patients have not been done systematically using individual rather than global assays. Such measurements can provide meaningful information on the status of tumor-host interactions and could potentially help in predicting thromboembolic and hemorrhagic tendencies. A complete fibrinolytic profile including total fibrinolytic activity (TFA), tissue plasminogen activator (t-PA), plasmin inhibitor (PI), plasminogen activator inhibitor (PAI), protein C (PC) and plasminogen (PLG) was obtained preoperatively in 114 brain tumor patients. PLG and PI did not show much variation among the groups. TFA was slightly reduced (15%) in patients with malignant brain tumors. t-PA, however, was abnormally low in several patients and in almost 40% of patients with brain metastasis. PAI was above the upper limit of normal in approximately 50% of the patients but particularly in glioma, glioblastoma and metastasis patients. Finally, mean PC was abnormally increased in the glioblastoma and metastasis groups (p less than 0.001). This is the first study that has measured protein C in brain tumor patients. In conclusion, plasma fibrinolytic levels show marked changes in a substantial number of brain tumor patients prior to surgery--suggesting an ongoing tumor-host interaction.

Brain Neoplasms↗
PubMed1991

Neurosurgery issues in oncology.

Advances in the surgical management of central nervous system neoplasms have been reported in several areas including the skull base, the spine and the stereotaxic applications in neurosurgery. A national survey of patterns of care for brain tumor patients contributed data on 11,185 patients, 97% of whom underwent surgery. Stereotaxic-guided craniotomies are providing added accuracy and shortened operative time and length of hospitalization, while the stereotaxic implantation of I125 seeds for recurrent high grade glioma has resulted in prolongation of survival between 54 and 81 weeks. Radiosurgery is being applied with increasing frequency and remarkable success in the management of skull base tumors, acoustic neuroma, and brain metastasis. The two prototypes used are the Gamma-knife and the linear accelerator-based multiple converging arcs technique. In the area of the skull base, significant anatomical details have been provided. Historical facts and clinical series related to the management of meningiomas and acoustic neuromas are reviewed. Spinal cord ependymoma is a surgically curable tumor as reported in a series of twenty-three patients followed for a mean of 62 months, and a randomized study has established the superiority of surgical resection for single brain metastasis as compared to the results obtained with radiation therapy alone.

Brachytherapy↗
PubMed1991

Observations regarding DNA replication sites in human cells in vivo following infusions of iododeoxyuridine and bromodeoxyuridine.

In studies using bromodeoxyuridine (BrdUrd) and/or iododeoxyuridine (IdUrd) to label S phase cells in cancer patients, several unique observations were made regarding DNA replication sites and the organization of newly synthesized DNA in post-mitotic cells. While the majority of tumour specimens removed at the end of infusions demonstrated concentration of replication sites around the nuclear membrane, biopsies obtained in leukaemic patients 1 week later demonstrated several distinct patterns of labelling. For example, one, two or all lobes of granulocytes were labelled. Scavenger macrophages bearing labelled leukaemic cells in their cytoplasm were also seen. Sequential IdUrd/BrdUrd labelling of solid tumours showed various patterns of nuclear/nucleolar/membrane labelling, allowing more precise localization of early versus late replication sites.

Antibodies, Monoclonal↗
PubMed1991

Biological significance of tissue plasminogen activator content in brain tumors.

Fresh brain-tumor samples were obtained at operation and analyzed for their content of tissue type plasminogen activator (tPA) using an activity assay (gel chromatography zymogram) and an enzyme-linked immunospecific assay. The specimens were taken from 23 glioblastomas, 35 metastatic tumors, 42 meningiomas, 16 low-grade gliomas, and seven acoustic neurinomas; seven specimens were from normal brain. A strong correlation was found between the results of the two assays (r = 0.77, p less than 0.0001). There was a threefold difference in the tPA content of the benign tumors as compared to malignant tumors (p = 0.0006), the latter having less tPA. Histologically benign meningiomas contained higher tPA than malignant meningiomas (p = 0.01); however, the difference between low-grade gliomas and high-grade gliomas was less evident. Overall regression analysis data have shown an inverse relationship between the tissue content in tPA and the presence and degree of tumor necrosis and peritumoral brain edema (p = 0.004 and p = 0.0004, respectively). This finding was most consistent in the glioblastoma group where the correlation coefficient values were r = 0.53 and r = -0.55, respectively. There was no significant correlation between the tissue tPA content and the age and sex, steroid use, or plasma tPA of the patients or the duration of symptoms. In summary, this is the first demonstration of tPA in a large series of human brain tumors and in normal brain. The differences observed have clear biological significance and, although the source of tPA in tumor tissue is still unknown, a relative reduction in tPA in tumor tissue may play an integral role in the development of tissue necrosis and tissue edema. The lack of tPA in tumor necrosis was not due to tissue destruction and cell death since urokinase was readily detectable in that tissue.

Brain Neoplasms↗
PubMed1990

Fibronectin.

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Amino Acid Sequence↗