The construction of a mouse/human chimeric antibody against human breast cancer cells.
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Amino Acid Sequence↗
Biomedical subjects
J Raus
Publications and source records attributed to J Raus.
Basement membrane components (matrigel) promote the tumorigenicity of human breast adenocarcinoma MCF7 cells and provide an in vivo model to assess the responsiveness of cells to estrogen.
The ability to transplant human tumors into athymic nude mice allows studies of tumor cells in vivo. However, after s.c. injection the incidence of tumor and metastases in nude mice is frequently low. We have studied the tumorigenicity in nude mice of estradiol (E2)-sensitive breast adenocarcinoma MCF7 cells. Matrigel, an extract of basement membrane proteins, induces rapid tumor development after s.c. injection of MCF7 cells. In the absence of this matrice, MCF7 cells failed to induce tumor growth. In this in vivo model, MCF7 cells were analysed for their E2 sensitivity. Two weeks after inoculation in the presence of matrigel, cells formed growing tumors in intact mice supplemented with E2. In ovariectomized or untreated mice, tumor appearance was delayed and the growth level was very low. Thus, MCF7 cells formed tumors in the absence of E2 but retained in vivo their responsiveness to estrogen. Growing human tumors in nude mice provides a rapid and useful model for testing the sensitivity of cells to hormone.
Adenocarcinoma↗
Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness.
1. Leukocyte enumeration through flow cytometry has revealed that severe depression may be accompanied by a systemic immune activation, indicative of an inflammatory response. The latter condition allegedly involves an important modification of acute phase plasma protein (APP) equilibrium. 2. In order to elucidate whether the state of severe depression is represented by alterations in APPs, the authors measured: alpha 1 antitrypsin (alpha 1 AT), alpha 2 macroglobulin (alpha 2 M), haptoglobin (Hp), alpha 1 acid glycoprotein (alpha 1 S), transferrin (Tf), complement component 4 (C4) and C-reactive protein (CRP). Interleukin-1-beta (II-1 beta) and interleukin-6 (II-6) circulating levels were determined. 3. Hyperhaptoglobinemia and hypotransferrinemia are hallmarks for major depression and depression per se, respectively. The disorders in Hp and Tf circulating levels are highly sensitive to (83%) and specific for (100%) melancholia as opposed to the healthy state. 4. Disorders in both APPs are significantly related to the absolute number of blood monocytes. 5. The authors observed a trend towards lower alpha 2M and higher alpha 1S values in severely depressed subjects. Severity of depression was significantly related to Hp and alpha 1S (both positively) and to alpha 2M and Tf (both negatively) values. 6. No significant intercategory differences in C4 could be established, whilst only a few subjects exhibited measurable CRP, II-1 beta and II-6 circulating levels. 7. Our findings may support the hypothesis that depression is accompanied by an inflammatory response.
Acute-Phase Proteins↗
Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining.
Several studies have reported a suppressed immune function (e.g. blast transformation) during depression. In an attempt to define the cellular basis of the reported immune disorders, the present study investigates the leukocyte cell subset profile of minor, simple major, and melancholic depressives, versus normal controls. We have counted the number of white blood cells (WBC) lymphocytes, monocytes, and granulocytes, while the number of lymphocyte (sub)populations has been identified by phenotype, using monoclonal antibody staining in conjunction with flow cytometry. The following cell surface antigens were determined: CD3+ (pan T), CD19+ (pan B), CD4+ (T helper/inducer), CD8+ (T suppressor/cytotoxic), CD4+CD45RA (T-memory cells), CD4+CD45RA+ (T-virgin cells), surface Ig, class II MHC HLA-DR, and CD25+ (IL-2 receptor). By means of pattern recognition methods, we established distinct immunological changes in minor and simple major depressed and in melancholic patients, setting them apart from the reference population. Depression, per se, is characterized by a higher number of WBC, monocytes, class II MHC HLA-DR, and memory T cells. Minor and simple major depressives exhibited an increased T helper/suppressor ratio. Increased numbers of IL-2 receptor bearing cells are a hallmark for major depression. Melancholics showed an increased number of pan T, pan B and T suppressor/cytotoxic cells. It was concluded that the established immune cell profile of depressed patients may point towards the existence of a systemic immune activation during that illness.
Adjustment Disorders↗
Decreased serum dipeptidyl peptidase IV activity in major depression.
It has been recently shown that severe depression is characterized by immune dysfunctions such as blunted mitogen-induced blast transformation, which is linked to interleukin-2 (IL-2) mechanisms, and to autoimmune responses. In order to explore one of the putative pathophysiological mechanisms underlying both factors, we have measured the predexamethasone and postdexamethasone serum dipeptidyl-peptidase IV (DPP IV) activity in depressed inpatients and normal controls. This enzyme is an important mediator of IL-2-related blast proliferation, and it may play a role in autoimmunity. We found significantly lower DPP IV levels in major depressives as compared with healthy controls, and melancholics exhibited significantly lower enzyme activity than minor depressives. There was a significant negative correlation between serum DPP IV activity and the severity of illness. However, we were unable to detect any significant relationships between DPP IV on the one hand, and mitogen-induced blast transformation, soluble IL-2 receptor accumulation in PHA culture supernatant, total number of leukocytes and lymphocytes, T lymphocytes, CD4+ and CD25+ cells, on the other. Men exhibited significantly higher serum DPP IV levels than women.
Adjustment Disorders↗
Determination of beta 2-receptor agonists in bovine urine and liver by gas chromatography-tandem mass spectrometry.
A highly specific and sensitive method for the simultaneous detection of seven beta 2-receptor agonists in bovine liver homogenates and urine was developed. A 10-g amount of liver was homogenized and treated with Subtilisin A. The resulting enzymatic digest was extracted with tert.-butanol-ethyl acetate (3:7) and the crude extract was purified on a 6-ml Bakerbond alumina neutral disposable extraction column. Subsequently, the hydrous eluate from the alumina column was buffered at pH 6 and loaded on top of a preconditioned 3-ml Bond-Elut Certify column. Urine was buffered and loaded onto a 3-ml Certify column without pretreatment. The analytes were eluted with dichloromethane-isopropanol (8:2) containing 2% ammonia. The extract obtained was trimethylsilylated and analysed by gas chromatography-tandem mass spectrometry using multiple selected reaction monitoring. The limits of detection for the beta 2-receptor agonists evaluated were between 0.5 and 5 ppb.
Adrenergic beta-Agonists↗
Coexisting dysregulations of both the sympathoadrenal system and hypothalamic-pituitary-adrenal-axis in melancholia.
In order to delineate putatively coexisting dysregulations between sympathoadrenal system and hypothalamic-pituitary-adrenal (HPA)-axis during depression, the authors measured the following: the pre and postdexamethasone (1 mg) 24 hr urine excretion of noradrenaline, dopamine, adrenaline, 3-methoxy-4-hydroxyphenylglycol (MHPG), free cortisol (UFC), and plasma cortisol. Melancholic patients were characterized by a significantly higher excretion of noradrenaline, dopamine and adrenaline, combined with significantly increased UFC, postdexamethasone plasma cortisol, and UFC values. We found significant and positive correlations between UFC on the one hand, and the 24hr urine excretion of noradrenaline, dopamine, and adrenaline, on the other. By the same token, we established significant relationships between the 24 hr urine excretion of those catecholamines and the postdexamethasone UFC and plasma cortisol values. Cortisol nonsuppressors exhibited a significantly higher excretion of noradrenaline, dopamine and adrenaline, as compared with cortisol suppressors. Dexamethasone administration did not have a significant effect on the urinary output of noradrenaline, dopamine, adrenaline or MHPG.
Adrenal Glands↗
Abnormal pituitary function during melancholia: reduced alpha-melanocyte-stimulating hormone secretion and increased intact ACTH non-suppression.
In order to investigate pituitary alpha-melanocyte-stimulating hormone (alpha-MSH), intact (1-39 structure) adrenocorticotropic hormone (ACTH), and adrenal cortisol secretion, we measured 8 a.m. plasma levels of those hormones before and after administration of 1 mg dexamethasone in 39 depressed inpatients and 10 healthy controls. We found a significantly lower baseline alpha-MSH secretion in melancholic patients as opposed to healthy controls. There were no significant relations between alpha-MSH secretion on the one hand and ACTH or cortisol secretion on the other. Dexamethasone did not affect the 8 a.m. alpha-MSH circulating levels. The post-dexamethasone intact ACTH and cortisol values were significantly higher in melancholics as compared with healthy, minor and simple major depressed subjects. ACTH non-suppression was defined as post-dexamethasone intact ACTH greater than or equal to 12 pg/ml. ACTH non-suppression was found to be more sensitive (70%) and specific (100%) for melancholia than cortisol non-suppression. By means of pathway analysis we have established that cortisol non-suppression during a severe depression is completely determined by an augmented ACTH escape from suppression by dexamethasone. It is concluded that the assay of post-dexamethasone intact ACTH could, in the future, replace post-dexamethasone cortisol determination.
Adjustment Disorders↗
Antiphospholipid, antinuclear, Epstein-Barr and cytomegalovirus antibodies, and soluble interleukin-2 receptors in depressive patients.
To determine whether depression might be associated with serologic indices of autoimmune processes or active virus infections, we measured the following parameters in healthy controls, minor, simple major and melancholic patients: antiphospholipid (anticardiolipin, antiphosphatidylserine), antinuclear, and Epstein-Barr (EBV) and cytomegalovirus (CMV) antibodies. In addition, the soluble interleukin-2 receptor (sIL-2R) circulating levels in serum were measured and used as a marker of T cell activation. The anticardiolipin antibody titers were higher in melancholics than in healthy controls and minor depressives. Antinuclear antibodies were present significantly more frequently in depressed patients than in normal volunteers. The anticardiolipin and antinuclear antibody titers were significantly and positively intercorrelated. Depression is characterized by increased serum circulating levels of sIL-2Rs compared to the healthy state. Antinuclear-positive subjects exhibited significantly higher sIL-2Rs than those without detectable antinuclear titers. There was a positive correlation between anticardiolipin activity and sIL-2Rs. We found no evidence that depression is linked to EBV or CMV infection.
Adult↗
A murine monoclonal antibody to human breast cancer cells associated with DNA ploidy status.
A murine monoclonal antibody, 5D10, raised against the human breast cancer cell line MCF7 reacted preferably with mammary carcinomas and weakly with normal epithelial cells. The antigens recognised by the antibody had molecular weights of about 28 and 90 kD. The reactivity of the antibody to human breast carcinomas correlated with the DNA ploidy status of the tumour cells. Upon analysis of 54 breast carcinoma specimens, the percentage of antibody positive cells was significantly higher in tumours with an aneuploid stemline than in those with a diploid DNA content (P less than 0.001). This antibody therefore could be a useful tool in evaluating the prognosis of breast carcinomas.
Antibodies, Monoclonal↗
HPA-axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls.
1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors. 2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed. 3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist. 4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), beta endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values. 5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.
Adrenocorticotropic Hormone↗
Cortisol escape from suppression by dexamethasone during depression is strongly predicted by basal cortisol hypersecretion and increasing age combined.
We determined baseline 0800h plasma cortisol concentrations, 24-hr urinary free cortisol (UFC) excretion, the post-dexamethasone cortisol values at 0800h and 1600h, and the 0800h dexamethasone concentrations in 60 depressed patients categorized according to the DSM-III. Up to 59% of the variability in the 0800h post-dexamethasone cortisol values could be explained by the multiple regression on UFC, 0800h basal plasma cortisol, age (all positively related), and dexamethasone concentrations (negatively related). The 1600h post-dexamethasone cortisol data were best explained (i.e., 55% of the variance) by the multiple regression on basal plasma cortisol, UFC (positive) and dexamethasone (negative). After controlling for UFC, baseline plasma cortisol, and age no significant effects of the depressive state (diagnostic classification or severity of illness) on the post-dexamethasone cortisol values could be detected. It can be deduced that cortisol non-suppression during depression is related strongly to baseline cortisol hypersecretion and increasing age. These factors are additive and contribute independently towards cortisol escape from suppression by dexamethasone.
Adult↗
A further exploration of the relationships between immune parameters and the HPA-axis activity in depressed patients.
In order to investigate the relationship between the immune apparatus and the hypothalamic-pituitary-adrenal (HPA)-axis activity in depressed patients, we measured in vitro lymphocyte responses to the mitogens Phytohaemagglutinin (PHA), Pokeweed (PWM) and Concanavalin A (Con A) and 8 a.m. baseline cortisol values in plasma, free cortisol excretion in 24 h urine (UFC), basal and post-dexamethasone beta-endorphin values. Major depressed patients with melancholia/psychotic features exhibited a significantly lower mitogen-induced blast transformation as compared to minor and simple major depressed patients. The lymphocyte responses to the three mitogens were significantly inversely related to baseline cortisol values and postdexamethasone beta-endorphin values. The proliferative capacity of lymphocytes to stimulation with PHA and PWM was significantly and positively related to UFC excretion. Up to 45% of the variance in the immune-responses to the mitogens was explained by the baseline cortisol, post-dexamethasone beta-endorphin and UFC values.
Adult↗
Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production.
In an attempt to delineate the pathophysiology underpinning the previously reported blunted lymphocyte responses to mitogenic stimulation in depressed patients, we measured the following immune variables in 28 depressives and 10 healthy controls: pre- and postdexamethasone (1 mg orally) lymphocyte responses to various mitogens, such as phytohaemagglutinin (PHA), and the PHA-induced accumulation of interleukin-1 beta (Il-1 beta) and soluble interleukin-2-receptors (sIl-2Rs) in culture supernatants. In the predexamethasone state, we found significantly more mitogen-stimulated blastogenesis in minor depressives vs healthy controls and major depressives. In depressed subjects there was a significant inverse relationship between the severity of illness and the mitogen-induced lymphocyte responses. Melancholics exhibited significantly more Il-1 beta accumulation in PHA culture supernatant than healthy controls. In healthy controls--but not in depressed patients--the sIl-2R accumulation perfectly reflects the magnitude of the PHA-induced lymphocyte stimulation. Dexamethasone administration significantly suppressed the lectin-induced blastogenesis and the Il-1 beta production rate in normal volunteers, whereas depressives exhibited dexamethasone nonsuppression in those factors. Healthy controls exhibited significantly less postdexamethasone blast transformation, Il-1 beta and sIl-2Rs accumulation in culture supernatant than the depressed patients.
Adult↗
A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and beta-endorphin in melancholic patients.
To investigate the relationships between pre- and postdexamethasone hypothalamic-pituitary-adrenal (HPA) axis functioning in depression, we measured the levels of baseline and postdexamethasone urinary free cortisol (UFC), plasma cortisol, adrenocorticotropic hormone (ACTH) and beta-endorphin. We found that dexamethasone significantly suppressed all hormone levels. All 4 postdexamethasone hormones--but not their baseline levels--were significantly higher in melancholic subjects than in minor and simple major depressives. We have accumulated evidence that the melancholic and minor depression groups form discrete classes in postdexamethasone HPA axis hormone levels; this supports the biological heterogeneity hypothesis of melancholia. We found that a combination of the postdexamethasone UFC and beta-endorphin values yielded the most significant diagnostic tool for melancholia. Our results suggest that the measurements of both hormones may constitute the most accurate index reflecting the HPA axis escape from suppression by dexamethasone in melancholia. By means of pathway analysis, we determined the causal relationships between age, dexamethasone circulating levels, diagnostic depression classification and the various baseline and postdexamethasone hormone values.
Adrenocorticotropic Hormone↗
Comparison of the affinities to bovine and human prothrombin of the staphylocoagulases from Staphylococcus intermedius and Staphylococcus aureus of animal origin.
Staphylocoagulases of Staphylococcus aureus (40 strains originally isolated from horses, dogs, cats, cows, sheep, opossums, pigs, humans, and a goat) and Staphylococcus intermedius (19 isolates from dogs and 1 pigeon strain) were tested for their affinity to prothrombins of either bovine or human origin. The tests used were the coagulase tube test (using human, bovine, or equine fibrinogen with either bovine or human prothrombin as the source of coagulase-reacting factor) and a chromogenic assay which enabled quantification of the amidolytic activity of the staphylocoagulase-prothrombin complex. S. intermedius showed weak specificity for human prothrombin, with 15% of the coagulases clotting human fibrinogen, 25% clotting equine fibrinogen, and 40% clotting bovine fibrinogen. However, 65% of coagulases clotted equine fibrinogen, 75% of coagulases clotted human fibrinogen, and 100% of coagulases clotted bovine fibrinogen when bovine prothrombin was used. The animal isolates of S. aureus displayed more diverse specificity toward prothrombin than S. intermedius strains. While 85% of coagulase preparations clotted human fibrinogen when human prothrombin was used, only 45% of preparations clotted bovine fibrinogen when bovine prothrombin was used. However, 62.5% of coagulases clotted human fibrinogen when bovine prothrombin was used and 85% of coagulases clotted bovine fibrinogen when human prothrombin was used. This may be a reflection of the diversity of the animal origins of S. aureus isolates.
Animals↗
Prediction of the DST results in depressives by means of urinary-free cortisol excretion, dexamethasone levels, and age.
This study investigates the relationships between cortisol escape from suppression by dexamethasone during a depressive episode, and the baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, circulating dexamethasone levels, and age. To this end, we measured urinary-free cortisol (UFC) excretion in 24-hr urine samples and the 8 AM cortisol and dexamethasone levels after administration of 1 mg dexamethasone in 50 depressive patients. We found that up to 54% of the variance in the postdexamethasone cortisol values could be explained by the multiple regression on UFC, age, and dexamethasone levels. By utilizing these three parameters, the dexamethasone suppression test (DST) nonsuppressor/suppressor state was correctly identified in 92% of the subjects. It was shown that an important part of the variance in postdexamethasone cortisol is actually background variance, irrelevant to depression and produced by the cumulative effects of the three aforementioned parameters. Only a small part (less than 20%) of the variance in postdexamethasone cortisol is determined by the actual depressive state. It was concluded that (1) baseline hypersecretion of cortisol, (2) decrements in the bioavailability of the test substance, (3) increasing age, and (4) the depressive state per se--all of which are cumulative--contribute independently to cortisol escape from suppression by 1 mg dexamethasone.
Adult↗
Effects of dexamethasone on the availability of L-tryptophan and on the insulin and FFA concentrations in unipolar depressed patients.
Several authors have shown that the availability of L-tryptophan (L-TRP) in the serum is lower in patients with major depression than in controls. It has recently been reported that the administration of a dose of dexamethasone sufficient to cause cortisol suppression also caused significant decrements in the availability of L-TRP. In order to elucidate the putative pathophysiological mechanisms underlying this decreased L-TRP disposition, the authors examined 37 depressed women categorized according to the DSM-III. L-TRP, the sum of five competing amino acids (CAA), the L-TRP/CAA ratio, and insulin and free fatty acid (FFA) levels were determined both before and after oral administration of 1 mg dexamethasone. The availability of L-TRP was significantly lower in depressed women with melancholia compared with simple major and minor depressives. The baseline disposal of L-TRP was related neither to insulin nor to FFA concentrations Dexamethasone administration significantly reduced the L-TRP and L-TRP/CAA values and increased FFA and insulin levels. Postdexamethasone L-TRP and FFA levels were significantly and positively correlated.
Adjustment Disorders↗