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S Jacobs

Publications and source records attributed to S Jacobs.

At least 19 recordsLinked to original sources
PubMed1992

Association of phosphorylated insulin-like growth factor-I receptor with the SH2 domains of phosphatidylinositol 3-kinase p85.

Insulin-like growth factor-I (IGF-I) stimulates the production of 3-inositides and markedly increases the phosphatidylinositol 3-kinase activity that is immunoprecipitated by anti-phosphotyrosine antibodies, a portion of which is also associated with the IGF-I receptor. In this study, recombinant p85, the regulatory subunit of phosphatidylinositol 3-kinase, and fusion proteins containing various subdomains were used to investigate the association of p85 with the IGF-I receptor and to demonstrate that p85 is a direct in vitro substrate of the IGF-I receptor kinase. Solubilized IGF-I receptor was immobilized on antireceptor antibody-agarose beads. Following in vitro receptor phosphorylation and incubation with cell lysate, immobilized receptor became associated with phosphatidylinositol 3-kinase activity and with protein bands with molecular masses of 85 and 110 kDa, which correspond to the known molecular masses of the subunits of phosphatidylinositol 3-kinase. These associations were inhibited by the addition of recombinant intact p85 or SH2-containing fusion proteins, but not by fusion proteins containing its SH3 domain or breakpoint cluster homology region. A fusion protein containing the SH2 domains of Ras GTPase-activating protein also inhibited the association of phosphatidylinositol 3-kinase activity with immobilized IGF-I receptor, although less effectively than p85, whereas a similar construct containing the SH2 domain of pp60src was without effect. When immobilized phosphorylated IGF-I receptor was incubated with intact p85 or the SH2-containing fusion proteins, it became associated with and phosphorylated these proteins. These results demonstrate that at least in vitro, a tight association occurs between phosphorylated IGF-I receptor and phosphatidylinositol 3-kinase, that the region of phosphatidylinositol 3-kinase that contains its SH2 domains is directly involved in this association, and that this region is a direct substrate for IGF-I receptor tyrosine kinase. Furthermore, these results suggest that Ras GTPase-activating protein can also interact with the IGF-I receptor and that different SH2 domain-containing proteins interact with the IGF-I receptor with widely differing affinities.

Animals↗
PubMed1992

Insulin/IGF-I receptor hybrids: a mechanism for increasing receptor diversity.

Insulin and IGF-I receptors are homologous disulfide linked alpha 2 beta 2 tetramers. These tetramers are formed biosynthetically when proreceptors containing alpha and beta subunits in a single uninterrupted linear peptide form disulfide linked homodimers and are subsequently proteolytically cleaved at the alpha-beta junctions. Cells expressing both receptors also express hybrid receptors that contain one insulin receptor alpha and beta subunit, and one IGF-I receptor alpha and beta subunit. These presumably form by the association of mixed proreceptors. Hybrid receptors greatly expand the possible repertoire of cellular responses to hormonal stimulation. Although not yet examined in detail, both the hormone binding and the signaling properties of the hybrid receptor appear to be different from that of either insulin or IGF-I receptor. Regulatory mechanisms that involve either insulin or IGF-I receptor, at the level of expression or subsequently, could alter the expression or function of the hybrid receptor or the other receptor. Similarly, pathology in one receptor could affect both the hybrid and other receptor, or perhaps be partially compensated for by a hybrid receptor. The magnitude of these effects could vary greatly in different tissues depending upon the relative level of expression of the different receptor forms. These postulated responses might explain some of the complex heterogeneity and linkage of these receptors that have been observed previously.

Animals↗
PubMed1992

Influence of aminoglutethimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione treatment.

The clinical and biochemical effects of combined treatment with the two aromatase inhibitors aminoglutethimide and 4-hydroxyandrostenedione were evaluated in 10 patients suffering from advanced breast cancer. All patients had become resistant to treatment with one of the drugs before having combined treatment. Seven patients progressing on 4-hydroxyandrostenedione who had aminoglutethimide added to their treatment and achieved a further suppression of plasma oestradiol by a mean of 40.0% (p < 0.05). Plasma oestrone was suppressed by a mean of 40.6% (p < 0.025) and plasma oestrone sulphate was suppressed by a mean of 63.6% (p < 0.025). Two of the patients, neither of whom had responded to 4-hydroxyandrostenedione alone, experienced objective tumour regression when aminoglutethimide was given in concert. Three patients progressing on aminoglutethimide who had 4-hydroxyandrostenedione added showed no further suppression of their plasma oestrogen levels, and no tumour regression was observed. These findings suggest a dose-response relationship between plasma oestrogen suppression at low postmenopausal levels and objective tumour response in breast cancer.

Adult↗
PubMed1992

The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation in breast cancer patients.

The influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA) given intramuscularly on the peripheral aromatisation of androstenedione into oestrone was investigated in postmenopausal women with breast cancer and compared with the suppression of plasma oestradiol (E2). 7 patients were investigated before and during treatment on day 7, i.e. midway between two weekly injections. After an intravenous injection of [3H] androstenedione and [14C] oestrone, urine was collected for 96 h and the isotope ratio determined in the urinary oestrogen metabolites after isolation with high performance liquid chromatography. At 250 mg, 4OHA inhibited aromatisation to [mean (S.D.)] 15.2 (5)% of baseline (P < 0.002). There was significantly greater inhibition to 8.1 (2.7)% at 4OHA 500 mg (P < 0.01). Plasma E2 was reduced to 41.2 (14.1)% of baseline at 4OHA 250 mg with a further reduction to 32.7 (19.8)% at 500 mg (P < 0.05). These results confirm the dose-response relation previously established with plasma oestrogen measurements alone.

Aged↗
PubMed1992

Aromatase activity, serum oestradiol and their correlation with demographic indices.

Peripheral aromatase activity was measured in 24 postmenopausal women suffering from advanced breast cancer. The % conversion of androstenedione to oestrone was then assessed for a significant correlation with age, weight, height, Quetelets index (weight/height2, Q.I.) and length of menopause. Serum oestradiol (E2) levels were measured in 22 of the subjects and compared with the same indices. There was no correlation between E2 or aromatase activity with the length of menopause (P = 0.3 and P = 0.5, respectively). In our data aromatase activity did not correlate with age (P greater than 0.5, n = 22). Serum E2 levels (P = 0.07, n = 20) expressed a negative correlation (i.e. decreased) with age. There was also a poor correlation between aromatase activity and weight of Quetelets index (P = 0.3, n = 20 for both). Serum E2 levels showed a statistically significant correlation with weight (P = 0.01, n = 21), but the relationship with Quetelets index just failed to attain statistical significance (P = 0.07, n = 20). In both cases the regression line was positive. When aromatase activity was correlated with serum E2 levels the regression line was positive but not statistically significant (P = 0.4, n = 22). The data indicate that aromatase activity is only one factor determining the differences in serum E2 levels between postmenopausal women.

Adult↗
PubMed1992

Aromatase inhibition: 4-hydroxyandrostenedione (4-OHA, CGP 32349) in advanced prostatic cancer.

We report the use of the steroidal aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA, CGP 32349), in the management of patients with advanced, hormone resistant, prostatic cancer. Eighteen of 25 patients (72%) showed a subjective response, mainly in the form of pain relief and increased performance. There were no objective improvements. A tumour flare occurred in 17/25 (68%). Detailed endocrine studies were performed during treatment. These showed that suppression of serum oestradiol levels occurred in 19/25 (76%) of patients during treatment with 4-OHA. Serum levels of androstenedione increased in 9/14 patients (64%). Concentration of serum testosterone and 5 alpha-dihydrotestosterone were elevated in 3/14 (21%) and 2/11 (18%) patients respectively. There appeared to be no correlation between response or tumour flare and changes in steroid levels during treatment with 4-OHA. The mechanism of action of 4-OHA in palliating patients with advanced prostatic cancer remains obscure. 4-OHA or its metabolites may be acting on metastatic bone metabolism via effects on oestrogen related osteoclastic and osteoblastic activity. Further investigation of the effects of aromatase inhibitors on prostatic biology, and bone metabolism in patients with metastatic prostate cancer, would appear worthwhile.

Aged↗
PubMed1992

The influence of aminoglutethimide and its analogue rogletimide on peripheral aromatisation in breast cancer.

The influence of the prototype aromatase inhibitor Aminoglutethimide (AG) and its analogue Rogletimide (RG) on peripheral aromatisation were investigated in 13 postmenopausal women with advanced breast cancer. Seven patients received AG 1,000 mg daily plus Hydrocortisone (HC) cover and six received RG as dose escalation of 200 mg bd, 400 mg bd and 800 mg bd. In vivo aromatase inhibition was investigated using the double bolus injection technique with [4-14C] oestrone ([4-14C]E1) and [6,7-3H] androstenedione ([6,7-3H]4A) followed by a 96 h urine collection. The labelled urinary oestrogens were separated and purified by chromatography and HPLC. Plasma oestradiol (E2) was also measured. AG mean aromatase inhibition was 90.6% +/- 1.8 s.e.m. and E2 suppression 75.7% +/- 7.3 s.e.m. RG mean aromatase inhibition was 50.6% +/- 9.8 s.e.m. at 200 mg bd, 63.5% +/- 5.7 s.e.m. at 400 mg bd and 73.8% +/- 5.8 s.e.m. at 800 mg bd. E2 suppression was 30.7% +/- 9.5 s.e.m., 40.2% +/- 10.3 s.e.m. and 57.6% +/- 9.2 s.e.m. respectively. These results confirm the efficacy of AG as an aromatase inhibitor. RG produced dose dependent E2 suppression and aromatase inhibition, but even at the maximum tolerated dose of 800 mg bd had sub-optimal aromatase inhibition and oestradiol suppression compared with AG.

Adult↗
PubMed1992

The Riyadh Intensive Care Program applied to a mortality analysis of a teaching hospital intensive care unit.

A computerised system of prediction of death using the Riyadh Intensive Care Program was applied retrospectively over a 17-month period to data collected prospectively on 1155 patients admitted to our intensive care unit. Variables which enable organ failure scores to be generated were recorded daily to make these predictions. Consultant medical opinion predicted that outcome was hopeless in 55% (115/209) of the patients who died. The predictive power of the computer demonstrated a sensitivity of 14.8% and a specificity of 99.8%. It is possible that the occurrence of three false predictions of death in the latter part of the series may have been related to a change in our antibiotic policy. We would be unhappy to recommend the general use of a computerised program for prediction of death without careful explanation of its significance and dangers.

Aged↗
PubMed1992

Optimization of the blood for oxygen transport and tissue perfusion in critical care.

In present practice, patients in intensive care are managed with subnormal haematocrit values and oligovolaemia. Optimization of the blood for oxygen transport in preterm infants in intensive care yields major benefits in their prognosis. A rational basis is described for this optimization in terms of the circulating blood volume and haematocrit, represented by circulating red cell volume (mass). Extrapolation of these lessons in haematological management is proposed for adult patients in critical care, so as to reduce dependence on respiratory support and minimize clinical complications and costs.

Adult↗
PubMed1992

Clinical and endocrine effects of leuprorelin acetate in pre- and postmenopausal patients with advanced breast cancer.

Premenopausal Study. Twenty-five pre- or perimenopausal patients with advanced breast cancer were treated with leuprorelin acetate 3.75 mg (n = 9) or 7.5 mg (n = 16) every 4 weeks. Serum levels of gonadotrophins and oestrogens were suppressed markedly by both doses and there was no indication that the lower dose was less effective as an oestrogen suppressant. There were four objective responders to the 3.75 mg dose and six to the 7.5 mg dose. Toxicity was confined almost entirely to hot flushes, which occurred in 17 patients. Leuprorelin acetate is therefore an effective agent in the treatment of premenopausal breast cancer patients. There appears to be no major detriment to the use of 3.75 mg rather than the 7.5 mg dose. Postmenopausal Study. Fifteen postmenopausal patients with advanced breast cancer were treated with monthly injections of leuprorelin acetate 7.5 mg to assess the clinical activity and endocrine responses to treatment. None of the 15 patients showed an objective response to treatment, although four patients had stable disease for at least 6 months. Endocrine effects after 4 weeks' treatment included major suppression of serum gonadotrophins to below 10% of pretreatment values and decreases in the level of serum testosterone in 12 of 14 patients. In this group there were no changes in oestradiol levels, although we had previously observed suppression in postmenopausal patients treated with goserelin. In common with other gonadotrophin-releasing hormone analogues, leuprorelin acetate cannot be recommended as a treatment for postmenopausal breast cancer.

Adult↗
PubMed1991

Pathologic grief and its relationship to other psychiatric disorders.

The authors defined explicit criteria for the diagnosis of pathologic grief, and used the criteria to examine the relationship between pathologic grief and two disorders: major depression and anxiety disorders (panic and generalized anxiety), in a sample of 25 bereaved persons. Sixty-four percent of the sample met the criteria for pathologic grief. Pathologic grief was only significantly associated with major depressive disorder. It was also associated with high scores on dimensional measures of anxiety and depression. The most frequent complication of bereavement appeared to be an anxious subtype of major depressive disorder that occurred in conjunction with severe, prolonged separation distress.

Adaptation, Psychological↗
PubMed1991

Limits of reproducibility of cross-sectional echocardiographic measurements of left ventricular muscle mass.

The total intrinsic variability of echocardiographically determined left ventricular muscle mass was evaluated in this study. Cross-sectional left ventricular echocardiograms were made in 13 normal volunteers (8 men, 5 women), ages 31 to 41 years (mean 36) with an interval period of about eleven months. We used the parasternal long axis view, the short axis view at the papillary muscle level and the four-chamber view from the apex. M-mode recordings were made from the parasternal long-axis view. Left ventricular muscle mass from M-mode recordings was calculated using a simple cube formula and from cross-sectional echo cardiography with an area-length formula. The reproducibility of the left ventricular muscle mass for the methods was respectively 10 +/- 6% and 5 +/- 3% (mean +/- SD). From both methods cross-sectional echo is the method of choice for determining left ventricular muscle mass in man in sequential studies.

Adult↗
PubMed1991

The influence of CGS 16949A on peripheral aromatisation in breast cancer patients.

The influence of a new aromatase inhibitor, CGS 16949A on peripheral aromatisation of androstenedione into oestrone was investigated in postmenopausal women with breast cancer. A mixture of 3H androstenedione and 14C oestrone was injected, and all urine was collected for the following 96 h. The isotope ratio was determined in the urinary oestrogen metabolites after isolation by HPLC. Eight patients were investigated before and during treatment with CGS 16949A. At a dose of 1 mg b.d. (eight patients) CGS 16949A inhibited aromatisation by a mean value of 82.4% (range 71.3 to 93.7%). When the drug dose was escalated to 2 mg b.d. (three patients) aromatisation was inhibited by a mean of 92.6% (range 90.6 to 95.8%), these results suggest that CGS 16949A at a dose of 1 mg b.d. causes submaximal aromatase inhibition in many patients, while a dose of 2 mg b.d. seems to result in greater than 90% aromatase inhibition. These data are consistent with previous observations that the higher dose is more effective in suppression of plasma oestradiol levels.

Aged↗
PubMed1991

A graded combination regimen for maintenance of gastric pH above 3.5 in critically ill patients.

Prophylaxis of acute upper gastrointestinal bleeding by control of gastric pH has been widely advocated for intensive care patients. H2-blockers and antacids have been used and demonstrated to be incompletely effective at maintaining gastric pH above 4. A study of 100 patients measured the efficacy of two-hourly gastric pH measurement and titrated therapy consisting of five levels: 1. no therapy 2. ranitidine 50 mg 8 hourly intravenously 3. ranitidine plus Mylanta 30 ml 2 hourly by nasogastric tube 4. ranitidine plus Mylanta 60 ml 2 hourly and 5. ranitidine 100 mg 8 hourly intravenously plus Mylanta II 60 ml 2 hourly. The level of treatment required by proportions of the total study group were (1) 15%, (2) 71%, (3) 96%, (4) 100%. Head-injured and intubated patients generally fell in the more resistant group while patients having had major elective surgery required lower levels of therapy. If control of gastric pH is to be uniformly achieved, a technique of titrated therapy based on gastric pH measurements is supported as cheaper and more effective than other standardised treatment regimens.

Adult↗
PubMed1991

Measurement of aromatisation by a urine technique suitable for the evaluation of aromatase inhibitors in vivo.

By modification of a recently developed method for separation of radio-labelled urinary oestrogens we were able to separate oestrogen metabolites and measure their isotope ratios in urine following injections of [3H]delta 4-androstenedione and [14C]oestrone. This method provides a useful tool for studying in vivo aromatisation of delta 4-androstenedione into oestrone in breast cancer patients before and during treatment with aromatase inhibitors.

Aminoglutethimide↗