Browsing by Author "Schulz, R."

In the departments of nuclear medicine, patients are treated with relatively large activities of (131)I for therapeutic purposes. The applied activities are in the range of 200-10 000 MBq. Consequently, individuals situated in the dwellings of the patients dismissed from the hospital are subjected to an external as well as an internal radioiodine exposition. Internal exposition is due to the inhalation of (131)I exhaled by the patients. In this article, the measurements of radioactivity exhaled by patients with various thyroid diseases, treated with (131)I in the department of Nuclear Medicine of the Radiological Centre in Goettingen and in the Hospital of Nuclear Medicine in Wuerzburg are presented. The measurements of activities exhaled by patients were repeated daily, up to 25 d after the treatment. In addition, the residual activities were monitored by measuring the external dose rates, and by measuring the (131)I activity in the urine of these patients. In some cases, the exhaled radioiodine was separated into three fractions: the elemental, the organically bound and the aerosol-bound iodine fraction. On the basis of the proposed measurements, the doses received by the family members of a discharged patient treated with (131)I were estimated by a model calculation.

To evaluate the therapeutical effects of the angiotensin converting enzyme inhibitor Captopril to the beta-blocker Propranolol in infants with congestive failure due to pulmonary overcirculation, we retrospectively analysed clinical, neurohormonal and hemodynamic data in 22 infants, 11 of whom were treated with Captopril (Group 1), 11 with Propranolol (Group 2). Age, weight, number of palliative operations, plasma renin activities and pulmonary to systemic flow ratios (3.5 vs. 3.5) were not significantly different prior to Captopril or Propranolol therapy. If treatment with digoxin and diuretics did not succeed, the infants were additionally treated with Captopril (1 mg/kg) for a mean of 7.4 months, or with 1.9 mg/kg Propranolol for 9.2 months. Results: 1 mg/kg Captopril did not effectively suppress angiotensin converting enzyme in the steady state at trough level (92+/-52 vs. 87+/-50 nmol/min/ml). In the Propranolol group, the clinical heart failure score (2.6+/-1.5 vs. 7.4+/-2.5) and plasma renin activities (14+/-10 vs. 101+/-70 ng/ml/h) were significantly lower, compared to the Captopril group. Length of hospital stay (23+/-9 vs. 52+/-24 days) was lower and weight gain (126+/-38 vs. 86+/-84 g/week) was higher within 3 months after starting Propranolol therapy. Significantly lower left atrial pressures (6.2+/-2.2 vs. 13.4+/-9.2 mmHg) and lower endiastolic ventricular pressures (7.6+/-2.5 vs. 12.6+/-4.0 mmHg) during pre-operative cardiac catheterization indicated a better diastolic ventricular function under chronic Propranolol treatment. Conclusion: Although high dose Captopril was not evaluated in this study, when compared to patients on low Captopril dosages, infants who received Propranolol treatment showed improvement in heart failure scores, shorter lengths of hospital stay, lower plasma renin activities and better diastolic ventricular functions. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Background - The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction. Methods and Results - Microembolization was induced by injecting microspheres (42-mum diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n = 7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n = 7) or 30 minutes after (n = 5) microembolization. In addition, chronically instrumented dogs received either placebo (n = 4) or methylprednisolone (n = 4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0 +/- 2.1% (mean +/- SEM) at baseline to 5.8 +/- 0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0 +/- 0.7% at 4 to 6 hours after microembolization back to baseline (19.1 +/- 1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction. Conclusions - Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.

Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer.

Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance(1-5). Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities(6-8). Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization(9-12). We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele(2)) and H/H (R172H allele(3)) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) (also known as Trp53(-/-)) littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.