Biomedical subjects

H Hermeking

Publications and source records attributed to H Hermeking.

27 records · Page 2Linked to original sources

PubMed1995

A complex between E2F and the pRb-related protein p130 is specifically targeted by the simian virus 40 large T antigen during cell transformation.

The p130 protein is a recently cloned member of the retinoblastoma protein family. We show here that transformation of NIH3T3-L1 fibroblasts (L1 cells) by the simian virus 40 large T antigen (LTAg) depends on the disruption of DNA binding complexes between transcription factor E2F and p130. LTAg binds to the pocket region of p130 in vivo and disrupts the E2F-p130 complexes. E2F-p130 complexes are present only in quiescent L1 cells and disappear at the G1/S phase boundary concomitantly to induction of DNA synthesis and expression of the E2F-regulated cdc2 gene. p130 is a substrate of cyclin-dependent kinase 2 (Cdk2) in vitro and associates with a Cdk in vivo which is activated upon serum stimulation in late G1. Overexpression of p130 inhibits cdc2 promoter activity and entry of quiescent L1 cells into S phase. The results demonstrate that p130 is negative regulator of cell cycle progression which is specifically targeted by LTAg during cell transformation.

3T3 Cells↗

PubMed1994

Role of c-myc in simian virus 40 large tumor antigen-induced DNA synthesis in quiescent 3T3-L1 mouse fibroblasts.

Stably transfected NIH 3T3-L1 mouse fibroblasts (L1 cells) expressing the simian virus 40 large tumor antigen (LTAg) maintain c-myc expression and proliferation in low serum, whereas cells expressing the mutant form LTAg-K1, defective in binding of the retinoblastoma suppressor gene product pRb, showed reduced levels of c-myc RNA and only background levels of DNA synthesis in low serum. The role of the c-Myc protein in LTAg-induced DNA synthesis was studied in microinjection experiments. Expression of LTAg induced cellular DNA synthesis in > 95% of microinjected serum-starved L1 cells, whereas the mutant LTAg-K1 could not induce DNA synthesis. Coexpression of dominant negative c-Myc or Max mutants with LTAg inhibited DNA synthesis, indicating that functional c-Myc is necessary for induction of DNA synthesis by LTAg. Expression of c-Myc induced programmed cell death (apoptosis) in serum-starved L1 cells. Coexpression of c-Myc with LTAg-K1 restored induction of DNA synthesis without apoptosis. Expression of a truncated LTAg, LTAg-(1-259), defective in binding of the tumor suppressor gene product p53, failed to prevent c-Myc-induced apoptosis. The data indicate that c-Myc can restore the ability of LTAg-K1 to induce DNA synthesis and that LTAg-K1 prevents c-Myc-induced apoptosis in serum-starved L1 cells by its interaction with p53.

3T3 Cells↗

PubMed1994

Mediation of c-Myc-induced apoptosis by p53.

The cellular proto-oncogene c-myc is involved in cell proliferation and transformation but is also implicated in the induction of programmed cell death (apoptosis). The same characteristics have been described for the tumor suppressor gene p53, the most commonly mutated gene in human cancer. In quiescent mouse fibroblasts expressing wild-type p53 protein, activation of c-Myc was found to induce apoptosis and cell cycle reentry, preceded by stabilization of p53. In contrast, in quiescent p53-null fibroblasts, activation of c-Myc induced cell cycle reentry but not apoptosis. These results suggest that p53 mediates apoptosis as a safeguard mechanism to prevent cell proliferation induced by oncogene activation.

3T3 Cells↗

PubMed1994

[Induced astigmatism in cataract surgery. Scleral tunneling incisions of 5.5 mm and 6.5 mm after 1-year follow-up].

To evaluate the effect of scleral pocket incisions closed with a single horizontal suture on postoperative astigmatism, 97 patients were enrolled in a prospective study. After 1 year of follow-up the data of 80 patients could be analysed. Routine phacoemulsification was performed in all patients consecutively by one surgeon. 40 patients received a posterior chamber lens with a 5 mm by 6 mm oval polymethylmethacrylate (PMMA) optic (group I), and 40 patients received an intraocular lens with a 6 mm diameter round PMMA optic (group II). The incisions were 5.5 mm and 6.5 mm, respectively. Follow-up visits including keratometry were scheduled 1 day, 5 days, 3 months, 6 months and 1 year postoperatively. The induced astigmatism was calculated using vector analysis. One day after operation the mean induced cylinder was 1.22 D in group I and 1.06 D in group II. After 5 days it amounted to 1.09 D (group I) and 1.03 D (group II), and at 3 months it was 1.07 D and 1.00 D, respectively. Six months after operation the induced cylinder was 1.04 D (group I) and 0.96 D (group II), and at 1 year it was 1.02 D and 0.81 D. There was no statistically significant difference between the groups at any time (Wilcoxon test, P > 0.05). We conclude that scleral pocket incisions closed with a single horizontal suture induce about 1 D of corneal astigmatism, with stability over time. There is no clinical advantage in reducing the incision width by using oval optics.

Aged↗

PubMed1993

In vitro study to elucidate the physical laws concerning the fragmentation of both solitary and multiple artificial stones.

These in vitro studies define the basic physical laws regarding work and energy for the successful fragmentation of human gallstones. For this purpose a standardized stone model was used consisting of plaster and glass microspheres with physical properties similar to those of human gallstones. All experiments were performed using the lithotripter model MPL9000 (Dornier). The acoustic energy passing stones of 10-30 mm ranged between 8 and 90 mJ per pulse depending on the stone size and energy setting. These results represent the basis for the three following investigations. In the first experiment the relationship between fragmentation and shock wave energy was investigated in a basket with 2 mm mesh size. Thus no layer of small fragments could shadow the acoustic energy for further fragmentation of larger fragments. A constant amount of stone material was found to be fragmented per shock-wave pulse irrespective of stone volume. A low energy threshold (2 mJ/cm3) was observed, below which fragmentation did not occur. In the second experiment, the sieve was covered with a membrane, thus simulating the in vivo situation. The presence of a layer of small fragments hindered the further disintegration of the larger fragments. The attenuation depended to a large extent on original stone volume and acoustic energy per pulse. The corresponding attenuation factor increased with the original stone volume. Thus the fragmentation of a stone with a diameter of 30 mm was attenuated twice as much as a stone of 20 mm size. The critical layer thickness at which no further disintegration took place was 2.5 mm at 18 kV, 4.2 mm at 22 kV, and 5.0 mm at 26 kV.(ABSTRACT TRUNCATED AT 250 WORDS)

Biophysical Phenomena↗

PubMed1993

Transcriptional and posttranscriptional regulation of human androgen receptor expression by androgen.

Autoregulation is a control mechanism common to several proteins of the steroid/thyroid hormone receptor superfamily. In this work, the effect of androgens and antiandrogens on the expression of the human androgen receptor (hAR) in prostate and breast cancer cell lines was studied. Northern blot analysis revealed a decrease in hAR steady state RNA levels in LNCaP cells by 3.3 nM of the synthetic androgen mibolerone. Maximal down-regulation of hAR RNA to 30% of control levels occurred 48 h after hormone addition. T47D breast cancer cells showed a similar effect with mibolerone, while hAR expression in normal skin fibroblasts did not respond to androgen treatment. As shown by nuclease S1 analysis, hAR transcripts initiate at three principal start sites, all of which are equally sensitive to androgen. Steroidal as well as nonsteroidal antiandrogens were capable of partially antagonizing androgen-mediated hAR RNA down-regulation in LNCaP and T47D cells, while not exerting a significant effect when administered alone. While hAR RNA stability was increased by hormone, nuclear run-on analysis revealed a 4-fold reduction of hAR gene transcription 96 h after androgen treatment. Although decreased hAR RNA levels did not coincide with a parallel decrease in AR protein levels, analysis of androgen-inducible reporter constructs demonstrated that prolonged androgen administration to cells results in a progressively impaired sensitivity of the intracellular androgen response mechanism. These results show that prolonged androgen exposure leads, besides its effect on hAR RNA levels, to functional inactivation of the AR. Thus, in vivo, posttranslational control of AR activity appears to be a novel mechanism of negative autoregulation of androgen effects on gene expression.

Androgens↗

PubMed1991

[Sclera fixation of posterior chamber lenses. Indications, technique and results].

Over 18 months we implanted posterior chamber lenses in 40 eyes using transscleral suturing. The indication for this technique was the absence of capsular support, in most cases due to previous cataract surgery and/or trauma. A uniform procedure was used. After a medium follow-up of 9 months the major complications were as follows: immediately after the operation transient keratopathia was present in a third of the cases; 6 eyes showed iritis, which persisted in 4 eyes. Other late complications were cystoid macular edema in 2 cases and central vein occlusion, retinal detachment and recurrent iritis in single cases. Despite these complications the functional results were favorable in 32 eyes with a best corrected vision of 6/12 or better. Poor visual outcome could be related to the operative procedure in 2 eyes and to pre-existing pathology in the remaining 6 cases. We conclude that the operative technique should be improved to reduce complications.

Follow-Up Studies↗

PubMed1990

[Daunomycin in vitrectomy of complicated diabetic retinal detachment].

Fourteen eyes with combined traction and rhegmatogenous retinal detachments from proliferative diabetic retinopathy were treated with pars plana vitrectomy (PPV) and daunomycin applied to the vitreous cavity using the technique described by Wiedemann et al. for the treatment of proliferative retinopathy. The operations were completed by filling the vitreous with silicone. The aim of our study was to investigate the effect of daunomycin and the reproliferation rate. After a follow-up period of at least 3 months, the post-operative results were compared with a control group of similar eyes treated with PPV and silicone tamponade alone. No evidence was found to the effect that daunomycin affects the rate of reproliferation.

Adult↗

PubMed1986

Response of human tumour xenografts to fractionated X-irradiation.

The response of two human tumour xenografts to single dose and fractionated X-rays has been tested using regrowth delay as the assay. The tumours were line transplanted cells from a moderately well-differentiated squamous carcinoma of the tonsillar fossa (XJ) and an undifferentiated carcinoma of the floor of the mouth (XR). Comparison of the dose response curves for single doses in air, clamped, or after misonidazole administration, led to estimates of the hypoxic fraction (approximately 15%) and the sensitizer enhancement ratio (less than or equal to 1.6). When 5 daily fractions were used, the effect of misonidazole (miso) was lost and reoxygenation appeared to be effective in both tumours. Comparison of single doses and 5 fractions in clamped tumours, and in those sensitized by miso, allowed the sparing effect of fractionation to be estimated. When analysed by the linear quadratic model the alpha/beta ratios were found to be in the range of 6.4-9.2 Gy and 6.8-16.0 Gy for the two tumours. These values are in good agreement with murine tumours (assayed in vivo or in vitro), with human tumour cells assayed in vitro, and with analyses of fractionated clinical data for skin cancer.

Animals↗