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Biomedical subjects

H Stahl

Publications and source records attributed to H Stahl.

At least 19 recordsLinked to original sources
PubMed2004

A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon beta-1a in the treatment of patients with active rheumatoid arthritis.

OBJECTIVE: To assess the efficacy of interferon beta (IFN beta) in combination with methotrexate in treatment of patients with rheumatoid arthritis. METHODS: 209 patients with active rheumatoid arthritis, who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry, were randomised in double blind fashion to receive placebo (0.05 ml or 0.5 ml), IFN beta 2.2 microg (0.05 ml), or IFN beta 44 microg (0.5 ml), given subcutaneously three times weekly for 24 weeks. The primary efficacy measure was a change in radiological scores at week 24. The secondary endpoint was the proportion of patients who met the ACR 20% improvement criteria at the end of the study. Synovial biopsy specimens were obtained before and after treatment from a subset of patients. Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis. Collagen crosslinks were measured in urine at different times throughout the study. RESULTS: Analysis of radiological scores and clinical variable showed no changes in any of the groups, and there were no differences between the groups. On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFN beta treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups. CONCLUSIONS: At the doses tested, treatment with IFN beta three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.

Adult↗
PubMed2004

Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs.

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity upon systemic administration in mice without showing the deleterious side effects observed with other apoptosis-inducing members of the TNF family such as TNF and CD95L. TRAIL may, thus, have great potential in the treatment of human cancer. However, about 60% of tumour cell lines are not sensitive to TRAIL. To evaluate the mechanisms of tumour resistance to TRAIL, we investigated hepatocellular carcinoma (HCC) cell lines that exhibit differential sensitivity to TRAIL. Pretreatment with chemotherapeutic drugs, for example, 5-fluorouracil (5-FU), rendered the TRAIL-resistant HCC cell lines sensitive to TRAIL-induced apoptosis. Analysis of the TRAIL death-inducing signalling complex (DISC) revealed upregulation of TRAIL-R2. Caspase-8 recruitment to and its activation at the DISC were substantially increased after 5-FU sensitisation, while FADD recruitment remained essentially unchanged. 5-FU pretreatment downregulated cellular FLICE-inhibitory protein (cFLIP) and specific cFLIP downregulation by small interfering RNA was sufficient to sensitise TRAIL-resistant HCC cell lines for TRAIL-induced apoptosis. Thus, a potential mechanism for TRAIL sensitisation by 5-FU is the increased effectiveness of caspase-8 recruitment to and activation at the DISC facilitated by the downregulation of cFLIP and the consequent shift in the ratio of caspase-8 to cFLIP at the DISC.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Rearrangement of structured RNA via branch migration structures catalysed by the highly related DEAD-box proteins p68 and p72.

RNA helicases, like their DNA-specific counterparts, can function as processive enzymes, unwinding RNA with a defined step size in a unidirectional fashion. Recombinant nuclear DEAD-box protein p68 and its close relative p72 are reported here to function in a similar fashion, though the processivity of both RNA helicases appears to be limited to only a few consecutive catalytic steps. The two proteins resemble each other also with regard to other biochemical properties. We have found that both proteins exhibit an RNA annealing in addition to their helicase activity. By using both these activities the enzymes are able in vitro to catalyse rearrangements of RNA secondary structures that otherwise are too stable to be resolved by their low processive helicase activities. RNA rearrangement proceeds via protein induced formation and subsequent resolution of RNA branch migration structures, whereby the latter step is dependent on ATP hydrolysis. The analysed DEAD-box proteins are reminiscent of certain DNA helicases, for example those found in bacteriophages T4 and T7, that catalyse homologous DNA strand exchange in cooperation with the annealing activity of specific single strand binding proteins.

Adenosine Triphosphatases↗
PubMed2000

Intertube coupling in ropes of single-wall carbon nanotubes

We investigate the coupling between individual tubes in a rope of single-wall carbon nanotubes using four probe resistance measurements. By introducing defects through the controlled sputtering of the rope we generate a strong nonmonotonic temperature dependence of the four terminal resistance. This behavior reflects the interplay between localization in the intentionally damaged tubes and coupling to undamaged tubes in the same rope. Using a simple model we obtain the coherence length and the coupling resistance. The coupling mechanism is argued to involve direct tunneling between tubes.

Journal Article↗
PubMed2000

Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family and has recently been shown to exert tumoricidal activity in vivo in the absence of any observable toxicity. The signaling pathways triggered by TRAIL stimulation and the mechanisms involved in resistance against TRAIL-mediated apoptosis are still poorly defined. We show here that TRAIL-induced apoptosis involves late dissipation of mitochondrial membrane potential (delta psi(m)) and cytochrome c release. These events follow activation of caspase-8 and caspase-3 and induction of DNA fragmentation. In addition, caspase-8-deficient cells are resistant against TRAIL-induced apoptosis, and inhibition of caspase-8 but not caspase-9 prevents mitochondrial permeability transition and apoptosis. In contrast, various Bcl-2- or Bcl-xL-overexpressing tumor cell lines are sensitive to TRAIL-induced apoptosis; however, they show a delay in TRAIL-induced mitochondrial permeability transition compared with control transfectants. This indicates that TRAIL-induced apoptosis depends on caspase-8 activation rather than on the disruption of mitochondrial integrity. Because most chemotherapeutic drugs used in the treatment of malignancies lead to apoptosis primarily by engagement of the mitochondrial proapoptotic machinery, we tested whether drug-resistant tumor cells retain sensitivity for TRAIL-induced apoptosis. Tumor cells overexpressing Bcl-2 or Bcl-xL become resistant to apoptosis induced by the chemotherapeutic drug etoposide. However, these cells are not protected or are only marginally protected against TRAIL-induced apoptosis. Thus, TRAIL may still kill tumors that have acquired resistance to chemotherapeutic drugs by overexpression of Bcl-2 or Bcl-xL. These data will influence future treatment strategies involving TRAIL.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Structure and expression of the human p68 RNA helicase gene.

Nuclear DEAD box protein p68 is immunologically related to SV40 large tumour antigen and both proteins possess RNA helicase activity. In this report, we describe the structural organisation of the human p68 gene and aspects of the regulation of its expression. Northern blot and primer extension analyses indicate that, although its level is variable, the p68 RNA helicase appears to be expressed from a single transcription start site in all tissues tested. Sequence analysis revealed that the p68 promoter harbours a 'TATA', a 'CAAT' and an initiator element and contains high affinity binding sites for Sp1, AP-2, CRE and Myc. This and functional promoter analyses in transient expression assays suggest that transcriptional regulation of the p68 gene is complex. Furthermore, there are indications that p68 expression is also regulated post-transcriptionally. Steady-state pools of poly(A)(+)RNA from human cells contain completely spliced p68 mRNA and alternatively spliced forms that contain introns 8-11 or 8-12 (from a total of 12 introns) and are not translated. Analysis of a conditionally p68-overproducing HeLa cell line points to negative autoregulation at the level of splicing, which is confirmed by a recently reported association of p68 with spliceosomes in human cells.

Alternative Splicing↗
PubMed1999

A chicken embryo protein related to the mammalian DEAD box protein p68 is tightly associated with the highly purified protein-RNA complex of 5-MeC-DNA glycosylase.

We have shown previously that DNA demethylation by chick embryo 5-methylcytosine (5-MeC)-DNA glycosylase needs both protein and RNA. Amino acid sequences of nine peptides derived from a highly purified 5-MeC-DNA glycosylase complex were identified by Nanoelectrospray ionisation mass spectrometry to be identical to the mammalian nuclear DEAD box protein p68 RNA helicase. Antibodies directed against human p68 helicase cross-reacted with the purified 5-MeC-DNA glycosylase complex and immunoprecipitated the glycosylase activity. A 2690 bp cDNA coding for the chicken homologue of mammalian p68 was isolated and sequenced. Its derived amino acid sequence is almost identical to the human p68 DEAD box protein up to amino acid position 473 (from a total of 595). This sequence contains all the essential conserved motifs from the DEAD box proteins which are the ATPase, RNA unwinding and RNA binding motifs. The rest of the 122 amino acids in the C-terminal region rather diverge from the human p68 RNA helicase sequence. The recombinant chicken DEAD box protein expressed in Escherichia coli cross-reacts with the same p68 antibodies as the purified chicken embryo 5-MeC-DNA glycosylase complex. The recombinant protein has an RNA-dependent ATPase and an ATP-dependent helicase activity. However, in the presence or absence of RNA the recombinant protein had no 5-MeC-DNA glycosylase activity. In situ hybridisation of 5 day-old chicken embryos with antisense probes of the chicken DEAD box protein shows a high abundance of its transcripts in differentiating embryonic tissues.

Amino Acid Sequence↗
PubMed1998

[Phase II study on preoperative radio-chemo-thermotherapy in locally advanced rectal carcinoma].

BACKGROUND: Recent studies show that preoperative radio-chemotherapy can increase resectability and local control of locally advanced rectal carcinomas. Additional regional hyperthermia might increase remission rates and tumor response. We therefore tested regional hyperthermia together with radio-chemotherapy in a phase-II study on locally advanced rectal carcinomas. PATIENTS AND METHODS: Thirty-seven patients with primary advanced stage uT3/T4 rectal carcinomas were treated with preoperative radio-chemo-thermo-therapy. The initial tumor depth was determined using endosonography, CT, and MRI. Radiotherapy was carried out in prone position (on a belly board) using standard techniques, with 5 x 1.8 Gy per week up to 45 Gy at the reference point. 5-Fluorouracil (300 to 500 mg/m2) was administered with low doses of leucovorin (50 mg) on days 1 to 5 and 22 to 28. The patients were treated with regional hyperthermia each week prior to radiotherapy and simultaneously with chemotherapy, using the Sigma 60 ring from the BSD-2000 system. Temperature/position curves and temperature/time curves were recorded in endocavitary (endorectal) catheters in tumor contact and as well in bladder and vagina. Following endosonographic restaging, the operation was carried out 4 to 6 weeks after the end of preoperative therapy and adjuvant chemotherapy continued in four cycles. In cases where tumors were non-resectable, a boost up to 64 Gy was aimed. RESULTS: Thirty-one of the 37 patients (84%) with primary carcinoma proved locally R0-resectable. In addition we had 1 R1-resection (3%) and 5 non-resectable tumors (13%). Among the resected tumors, 53% experienced a reduction of depth infiltration from the initial endosonographic stage during preoperative therapy. The actuarial survival rate after 4 years is 65% (free of progression 57%). The actuarial 4-year survival rate was particularly favorable for the group of responders. Overall, the preoperative multimodal therapy was well tolerated, and premature termination was only necessary in 1 case (3%). Grade III/IV toxicities in the intestine and skin were reduced as far as possible by field blockings and cooling of the perineal region. They occurred only in 5/37 patients (13%) at the intestine and in 6/37 patients (16%) at the skin. The thermal data were subjected to a statistical analysis. The quality of temperature distribution (T90, cum min T90 > or = 40.5 degrees C) depends on the power level and relative power density. The response (reduction of tumor size or depth infiltration) correlated significantly with quality parameters of the temperature distributions. This dependency is found as a trend for progression-free survival, too. CONCLUSIONS: Preoperative radio-chemo-thermo-therapy proved to be practical and effective, with encouraging remission rates and excellent local control rates. For this reason, a phase-III study to test regional hyperthermia has been initiated. At the same time, certain technical improvements are still under development for regional hyperthermia.

Adult↗
PubMed1998

[Radiotherapy of exudative senile macular degeneration. A prospective controlled study].

UNLABELLED: Despite the successful therapy of subretinal neovascular membranes by laserphotocoagulation there are many problems to be overcome. In the case of subfoveolar neovascularization, photocoagulation leads to a sudden decrease in visual acuity. Recently radiotherapy is considered as an alternative. Complications and effectivity were evaluated in this prospective and randomized trial. The initial results are presented. PATIENTS AND METHODS: There are 76 patients (51 women, 25 men, average age 77.7 +/- 8.6 years) included in the prospective randomized study. All of them show subfoveolar neovascular membranes in FLA and a decrease in visual acuity between 0.05 and 0.5. They were randomly assigned to either the radiotherapy or the control group. Radiotherapy was done within 6 days by 6 x 2 Gy (6 MV photons). The follow-up was at 4 weeks, after 3 months, after 6 months and then every 6 months after the end of radiotherapy. On average the follow-up is at 15.1 months. RESULTS: Concerning age and visual acuity before therapy, the control group and the radiotherapy group were not significantly different. At 4 weeks after radiotherapy, visual acuity was 0.13 +/- 0.46 (LogMAR). After 12 months, visual acuity at a distance was 0.11 +/- 0.30 in the therapy group and 0.09 +/- 0.13 (P = 0.838) in the control group. Patients with a preoperative visual acuity better than 0.2 improved more after radiotherapy. Metamorphopsy improved in 75% of the therapy group. The following complications could be observed: In the control group 3 patients suffered subretinal bleeding, in the radiotherapy group 3 patients, respectively. CONCLUSIONS: At present, the follow-up is too short to recommend radiotherapy as a standard procedure in the case of subfoveolar neovascularization. The results in patients with a better preoperative visual acuity encourage us to continue this study.

Aged↗
PubMed1998

Treatment of squamous cell carcinomas of the floor of the mouth and tongue by interstitial high-dose-rate irradiation using iridium-192.

The results are presented of afterloading high-dose-rate-radiation with iridium-192 in 34 patients with squamous cell carcinomas of the floor of the mouth and tongue. Some patients were also treated surgically or given percutaneous radio- or chemotherapy. At the time of diagnosis, 28.0% had a T2 tumour, 41.9% a T3 tumour and 30.1% a T4 tumour, 41.2% had positive lymph nodes and 2.9% distant metastases. The response rate was 64.7%, 26.5% of which were complete remissions and 38.2% partial remissions. In 61.8% of cases, the tumour was recurrent and responded with a rate as high as 57.2%, 23.9% of which were complete remissions and 33.3% partial remissions. Survival times were dependent upon therapy results. The mean survival of patients with complete remission was 40.3 months, with partial remission 16.1 months as opposed to 7.2 and 3.5 months respectively in patients showing no change or progressive disease. It can be concluded that afterloading therapy using high-dose-rate-radiation with iridium-192 achieves good palliative results and should be looked at as a supplementary treatment modality for squamous cell carcinomas of the floor of the mouth and tongue.

Adult↗
PubMed1997

[A phase-I/II study on the local hyperthermia of cervical N2/N3 lymph node metastases].

BACKGROUND: Patients with advanced lymph node metastases from head and neck tumors at stage N2/N3 (i.e. UICC IV) present a difficult therapeutic problem. Despite combined radio-chemotherapy and hyperfractionated and/or accelerated fractionation regimens, local control of these tumors remains unsatisfactory. For this reason, the value of local radio wave/microwave hyperthermia was examined for this patient group in a phase I/II study.

Adult↗
PubMed1996

[How did the AIDS virus develop? Scientific knowledge and philosophical suppositions].

Several years after the occurrence of the first cases of AIDS, the HIV retrovirus was discovered in the eighties. How did this terrible virus come into being? 'A punishment from God' say some. 'A new life form created by man using gene technology', say others. Most scientists, however, do not share these views. They assume that spontaneous, random gene mutations are responsible for the AIDS virus. Viruses change their qualities frequently and new variations are constantly being created. Some philosophical conclusions from these findings are discussed.

Genetic Techniques↗
PubMed1996

Local hyperthermia of N2/N3 cervical lymph node metastases: correlationof technical/thermal parameters and response.

PURPOSE: Patients with advanced head and neck carcinomas, primarily nonresectable as well as recurrent cases, were treated in multimodality regimens with radiotherapy, chemotherapy, and local hyperthermia. Commercially available microwave and radiowave applicators were used in 50 patients with N2/N3 cervical lymph node metastases during more than 250 heat treatments. To assess technical suitability, the achieved power densities and thermal parameters were tested for correlation with anatomical and geometrical factors. To assess effectiveness, the response was compared with derived parameters of the achieved temperature distributions. METHODS AND MATERIALS: The temperature measurement points (in thermometry catheters) documented by computerized tomography are labeled according to tissue depth, shielding by osseous structures, and location in relation to the external applicators. Relative and absolute specific absorption rates (SAR) and cooling coefficients are extracted from the temperature-time curves. Time-averaged temperature-position curves are evaluated to obtain index temperatures (T90, T50, T20), minimum/maximum tumor temperatures, cumulative minutes T90 > or = 43 degrees C, and 43 degrees C-equivalent min T90. Radiation dose, treatment time, and chemotherapy regiment are also considered. A response parameter is defined using the pre- and posttherapeutic tumor volumes. A multivariate variance analysis is performed for the dependent variables power density, thermal parameters, and response. RESULTS: A significant correlation exists between power density and absorption, presence of a fat layer, and applicator illumination. The maximum depth is 5 cm, where SAR of >= 10 mW/g are registered. Achieved temperatures at individual measurement points are dependent on the SAR, and to a lesser extent, the perfusion-dependent cooling coefficients, but the index temperature T90 is only significantly related to intratumorally achieved SAR. The thermal gradient (T20-T50) and temperature peak (T20) are significantly influenced by the tumor volume. The response is directly related to the index temperature T90, equivalent minute T90 43 degrees C, and cumulative minutes T90 > or = 40.5 degrees C, and inversely related to the tumor volume. CONCLUSIONS: Local hyperthermia using microwave and radiowave applicators in the head and neck region is a tolerable and clinically practical supplementary therapy used as part of multimodal regimens, and has already been proven to be effective. However, the analyses also demonstrated the limits of currently available technology, and confirm the need for continued methodical research.

Adult↗
PubMed1996

Hyperthermia in the multimodal therapy of advanced rectal carcinomas.

The synergistic effects of hyperthermia (raising temperatures to 40 degrees C and above) when combined with radiotherapy and cytotoxic drugs and a modulation of immunological phenomena have been demonstrated in the laboratory. Pre-clinical data relating to hyperthermia are summed up, along with their implications for clinical application. Controlled studies of local and regional hyperthermia have been performed during recent years, and these show us that the adjunction of hyperthermia provides at least an improvement of local control compared with radiotherapy alone. Current clinical results are summarized. Therapy systems based on radiowave irradiation have been commercially available for regional hyperthermia of the pelvis since the mid 1980s. This technology allows us to perform sufficiently tolerable and effective regional hyperthermia on rectal carcinomas. Used as part of curative preoperative and postoperative multimodal therapeutic strategies, hyperthermia can lead to improvement in local control (resectability, down-staging, progression-free time, recurrence rate), at least for certain risk groups. The preoperative radio-chemo-thermotherapy of advanced primary and recurring rectal carcinoma, uT3/4, was tested in a phase-I/II study of 20 patients. Therapy procedure, acute toxicity, thermal parameters, and response are described and discussed for this patient group. The regimen proved to be sufficiently tolerable, and complications did not occur. Tumor resection was performed on 14 of the 20 patients; 13 of the procedures were R0-resections and one was an R2 resection. In 64% of the resected rectal carcinomas, histopathological down-staging of the pretherapeutic endosonographical stadium was achieved; in three of the patients, despite continued non-resectability, local control has now been maintained for more than 12 months. In two patients with nonresectable rectal carcinomas, local progress was seen during the neoadjuvant combination therapy.

Clinical Trials as Topic↗
PubMed1995

Unwinding of chromatin by the SV40 large T antigen DNA helicase.

We have analysed the unwinding of nucleosomally organized DNA by simian virus 40 large tumour (T) antigen. Isolated T antigen can bind to existing nucleosome cores containing the viral replication origin sequence, which results in displacement of the histone octamer and unwinding of the DNA. However, specific binding to nucleosome cores is salt sensitive and nearly completely blocked under ionic conditions that otherwise support DNA replication. Once started, the progressing T antigen helicase, like an elongating RNA polymerase, is not further repressed by histone octamers, irrespective of the presence or absence of linker histone H1. Disruption of the nucleosomal structure in the process of unwinding may be assisted by the demonstrated interaction of the hexameric T antigen complex with histone proteins H1 and H3. Finally, our studies reveal the inability of topoisomerase I and/or II to continually relieve the superhelical tension of covalently closed circular minichromosomes as generated during their unwinding by T antigen. This may indicate that chromatin relaxation during the process of DNA replication can only be efficiently performed by a topoisomerase that is (trans)activated by other factors.

Adenosine Triphosphate↗
PubMed1995

[The use of an early postoperative interstitial-hyperthermia combination therapy in malignant gliomas].

BACKGROUND: The survival of people suffering from malignant gliomas (WHO level III and IV) is predominantly limited by local progress in the primary tumor region. Interstitial hyperthermia combined with radiotherapy or chemotherapy is one approach for the intensification of local therapy. It is possible to combine (partial) tumor resection with hyperthermia as well as with brachytherapy by implanting catheters intraoperatively. PATIENTS AND METHODS: A pilot study was performed to examine practicality, tolerability, effectiveness and scope for improvement in early postoperative hyperthermia treatment following catheter implantation as part of (partial) tumor resection. Each CT data set was transferred into a VAX 3100 workstation for retrospective analysis of the hyperthermia treatment. The implanted catheters were segmented and the distributions of power density and temperature were simulated. We sought to achieve the best possible temperature distributions by optimising the catheter arrangement in the planning calculations. The corresponding Ir-192-source brachytherapy treatments were simulated in a similar way using the implanted, as well as optimised catheter arrays. RESULTS: Intraoperative catheter implantation in 4 patients was problem-free. Postoperative complications were not observed, neither were infections. Interstitial microwave hyperthermia in combination with percutaneous irradiation or chemotherapy a few days after the operation was also tolerated well by all patients. Effective temperatures (of at least 42 degrees C) were regularly achieved at measurement points, but the temperature distributions were unsatisfactory, with T90 values (the temperature reached in at least 90% of the target volume) of under 38 degrees C. Measured temperature/position curves showed qualitative correlation with the simulated calculations. The catheter positions determined by optimisation varied significantly from the positions clinically used. CONCLUSIONS: Early postoperative combination therapy using hyperthermia for the treatment of malignant gliomas is a very practical approach. The optimisation strategies described should be used preoperatively to plan catheter arrays for interstitial hyperthermia and brachytherapy, and these arrays should be implanted using stereotaxic surgery.

Antineoplastic Agents↗
PubMed1995

[Magnetic resonance tomography of finger polyarthritis: morphology and cartilage signals after ademetionine therapy].

This report deals with a prospective study of 21 patients with finger osteoarthritis treated over a period of three months with either Ademetionin (therapy group: 14/21) or without (control group: 7/21). MR-Imaging was carried out before and after treatment using spin-echo and 3D-Flash sequences. Morphological parameters and signal intensity changes of the hyaline cartilage were evaluated. The increase of the cartilage signal intensity was significant in the therapy group, this can be interpreted as an structural improvement. Also a decrease of the cartilage signal intensity with age was found. The morphological parameters showed no significant changes in the therapy and control groups.

Arthritis, Rheumatoid↗