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R Schnell

Publications and source records attributed to R Schnell.

At least 19 recordsLinked to original sources
PubMed2006

Application of the use of high-throughput technologies to the determination of protein structures of bacterial and viral pathogens.

The Structural Proteomics In Europe (SPINE) programme is aimed at the development and implementation of high-throughput technologies for the efficient structure determination of proteins of biomedical importance, such as those of bacterial and viral pathogens linked to human health. Despite the challenging nature of some of these targets, 175 novel pathogen protein structures (approximately 220 including complexes) have been determined to date. Here the impact of several technologies on the structural determination of proteins from human pathogens is illustrated with selected examples, including the parallel expression of multiple constructs, the use of standardized refolding protocols and optimized crystallization screens.

Animals↗
PubMed2006

[Secondary malignancies after successful primary treatment of malignant Hodgkin's lymphoma].

Malignant Hodgkin's lymphoma (HL) has become a curable disease through the increasing intensity of the treatment strategies applied. These regimens are aggressive, including radiotherapy and chemotherapy leading to the possibility of secondary malignancies. The German Hodgkin Lymphoma Study Group considered three cohorts including 5,411 patients with all stages of HL. In 127 patients a secondary solid tumor was diagnosed (cumulative risk 2%, median follow-up 72 months), with bronchial carcinomas (23.6%) and colorectal adenocarcinomas (20.5%) being the most frequent neoplasms. Secondary acute myeloid leukemia was found in 36 patients, another ten developed myeloid dysplasia (cumulative risk 1%, median follow-up 55 months). A total of 52 patients revealed a non-Hodgkin's lymphoma (NHL; cumulative risk 0.9%, median follow-up 46 months). The overall incidence of secondary malignancies was 3.9% in patients who had been treated successfully for their HL with radio- and/or chemotherapy.A secondary NHL can be particularly difficult to be distinguished from the preceding HL. Therefore, in case of a suspected relapse, a complete histopathological work-up must be performed.

Antineoplastic Agents↗
PubMed2005

Immunotherapy of Hodgkin's lymphoma.

Many new treatment approaches have given promising results in experimental Hodgkin's lymphoma (HL) models. Early clinical trials evaluating antibody based compounds as immunotoxins (ITs), radioimmunotherapy (RIT), bispecific molecules (BSMs), and recently monoclonal antibodies (MAbs), have demonstrated some clinical efficacy in patients with advanced refractory or relapsed HL. In addition, cellular immunotherapy is evolving. Although it seems unlikely to cure chemotherapy resistant patients with larger tumor masses by either of these approaches alone, the combination with conventional chemotherapy might help to overcome resistance of Hodgkin-/ReedSternberg (H-RS) cells. Another rationale for the development of these immunotherapies is to eliminate residual disease and thereby to prevent relapses from the disease. Currently, several clinical studies are running. A murine MAb (Ki-4) based 131 Iodine conjugate has shown efficacy in refractory HL patients in a phase II study, but less toxic constructs using alternate MAbs or isotopes should be developed. A humanized as well as a fully human anti-CD30 MAb are being tested in clinical phase I/II studies. These MAbs could engage the human immune system against the H-RS cells. In addition, these MAbs could be then combined with conventional chemotherapy in order to improve the treatment of HL.

Animals↗
PubMed2005

[Radioimmunotherapy with yttrium-90 ibritumomab tiuxetan. Clinical considerations, radiopharmacy, radiation protection, perspectives].

90Y-ibritumomab tiuxetan (Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory follicular non-Hodgkin's lymphoma pretreated with rituximab. Future directions are the combined use of 90Y-ibritumomab tiuxetan as part of the initial treatment and as first-line multi-agent therapy of relapsed disease. Current studies investigate patients with other than follicular indolent histologies, e. g. diffuse large cell lymphoma. Labelling of 90Y ibritumomab tiuxetan is a safe procedure, the radiochemical purity is not disturbed by a higher room temperature or by metallic impurity. Quality control is recommended by thin layer chromatography (TLC), strips >15 cm are favourable. TLC cannot distinguish between the correctly radiolabelled antibodies and radiocolloid impurity. If necessary, additional HPLC should be performed. Radiocolloid impurities are absorbed to the solid phase and do not reach the eluate. If the radiochemical purity test is insufficient (<95%), the additional cleaning using EconoPac 10 DG columns (Biorad, Hercules, CA, USA) is a reliable procedure to reduce the percentage of free radionuclide. However, this procedure is not part of the approval.

Anemia↗
PubMed2004

A dominant linear B-cell epitope of ricin A-chain is the target of a neutralizing antibody response in Hodgkin's lymphoma patients treated with an anti-CD25 immunotoxin.

Hodgkin's lymphoma patients treated with an anti-CD25 Ricin toxin A-chain (RTA)-based Immunotoxin (RFT5.dgA) develop an immune response against the toxic moiety of the immunoconjugate. The anti-RTA antibody response of 15 patients showing different clinical features and receiving different total amounts of RFT5.dgA was therefore studied in detail, considering antibody titre, IgG and IgM content, average binding efficacy and ability to inhibit in vitro the cytotoxicity of a RTA-based Immunotoxin. No correlations were found between these parameters and the clinical features of the patients or the total amount of Immunotoxin administered. However, using a peptide scan approach we have identified a continuous epitope recognized by all patients studied, located within the stretch L161-I175 of the RTA primary sequence, close to a previously identified T-cell epitope. The ability of anti-L161-I175 antibodies to recognize folded RTA and to affect the biological activity of RTA by inhibiting RTA-IT cytotoxicity in vitro revealed that they may exert an important role in IT neutralization in vivo. Discovery of RTA immunodominant epitopes which are the target of anti-RTA immune response may lead to the development of immunomodulating strategies and to more successful treatment schedules.

Antibodies↗
PubMed2003

[Assessing the impact of delivery unit size on neonatal survival: estimation of potentially avoidable deaths in Hessen, Germany, 1990-2000].

BACKGROUND AND OBJECTIVE: There are only few analyses from Germany on the impact of delivery unit size on neonatal outcome. The objective of this study was to evaluate the influence of delivery unit size on neonatal survival in Germany. PATIENTS AND METHODS: Data from the perinatal birth register for Hessen for 1990-2000 comprising 640554 births, and the Neonatal Survey for 1989-1997 in Hessen were used. Potentially avoidable deaths were assessed according to delivery unit size and birth weight category. Additionally trend analyses and an extrapolation to potentially avoidable deaths in all of Germany were performed. RESULTS: Compared to large delivery units, smaller ones showed higher risk adjusted mortality rates. Calculation of potentially avoidable deaths gave an estimate of 257 early neonatal deaths in 11 years. Although trend analyses revealed a decline of potentially avoidable deaths, an extrapolation of such deaths for all of Germany still yielded an estimate of more than 300 potentially avoidable deaths per year using data from 1997-2000 only. CONCLUSION: A valid inference as to the magnitude of the observed effect remains even in the face of a very cautious interpretation of our results. During the study period of 11 years, more than 200 neonatal deaths could be attributed to the fact that births in Hessen are dispersed among many small hospitals. If this pattern of births in small units is common throughout Germany, it suggests that several hundred neonatal deaths per year may be attributed to this risk factor when extrapolating these results nationally. Further research is necessary to describe the nation-wide magnitude of this problem and to identify the role of underlying causal risk factors more precisely. Additionally policy discussions regarding structural changes in obstetrical care should be undertaken in the meantime, aimed at reducing the observed mortality rates.

Birth Weight↗
PubMed2003

Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin's lymphoma.

BACKGROUND: Immunotoxins (ITs) consist of cell binding ligands coupled to toxins or their subunits. Hodgkin's lymphoma (HL) is an excellent target for ITs since lymphocyte activation markers such as CD25 and CD30 are expressed in large numbers. The ITs RFT5.dgA (anti CD25) and Ki-4.dgA (anti CD30) were constructed by linking the monoclonal antibodies RFT5 and Ki-4 to deglycosylated ricin A-chain (dgA). Both ITs showed potent specific activity against HL cells in vitro and in vivo in animal models, and were subsequently evaluated in phase I/II clinical trials in humans. PATIENTS AND METHODS: In two separate trials, the ITs were administered i.v. four times every other day over 4 h. The objectives of the phase I trials included the determination of the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, antitumor activity and immune response against the IT. RESULTS: Twenty-seven patients with refractory HL were included in the phase I/II study of RFT5.dgA and 17 patients were included in the phase I study of Ki-4.dgA. The MTD of RFT5.dgA was 15 mg/m(2), whereas that of Ki-4.dgA was 5 mg/m(2). DLTs were related to vascular leak syndrome, consisting of edema, tachycardia, dyspnea, weakness and myalgia. Measurement of serum levels of RFT5.dgA demonstrated a C(max) of 0.2-9.7 micro g/ml with a half-life (t()) varying from 4 to 10.5 h. Peak serum concentration of Ki-4.dgA ranged from 0.23 to 1.7 micro g/ml. In both trials approximately 60% of patients developed human anti-mouse and/or anti-dgA antibodies. Seventeen of 18 patients treated at the MTD of RFT5.dgA were evaluable for clinical response. Responses included two partial remissions (PR), one minor response (MR) and five stable diseases (SD). Fifteen of 17 patients treated with Ki-4.dgA were evaluable for clinical response. Responses included one PR, one MR and two SD. CONCLUSIONS: RFT5.dgA and Ki-4.dgA showed moderate efficacy in heavily pretreated refractory patients with HL. Ki-4.dgA was less well tolerated than RFT5.dgA. This might be due, at least in part, to the formation of Ki-4.dgA/sCD30 complexes.

Adult↗
PubMed2003

[Hodgkin's lymphoma in nuclear medicine: diagnostic and therapeutic aspects].

Today, diagnostic and therapeutic strategies of Hodgkin lymphoma (HL) with positron emission tomography and radioimmunotherapy include state-of-the-art nuclear medicine which require the cooperation between oncology and nuclear medicine. The benefit of FDG-PET in HL patients with residual tumor masses consists of its high negative predictive value in the therapy control of the disease. The concept of waitful watching in patients with PET-negative residual masses after BEACOPP-chemotherapy will be evaluated in a large multicenter trial of the GHSG (German Hodgkin Study Group). Radioimmunotherapy has been performed in patients with CD20-positive Non-Hodgkin lymphoma for 10 years with promising results. HL is also an excellent target for immunotherapy due to the expression of antigens such as CD25 and CD30. Thus, a new radioimmunoconstruct consisting of the murine anti-CD30 antibody Ki-4 labeled with iodine-131 was developed for patients with relapsed or refractory HL.

Fluorodeoxyglucose F18↗
PubMed2002

Mitochondrial DNA restriction map for the Caribbean fruit fly, Anastrepha suspensa, and occurrence of mitochondrial DNA diversity within highly inbred colonies.

A restriction map has been constructed for Anastrepha suspensa mitochondrial DNA. One HaeIII site was found to be polymorphic among individuals in highly inbred colonies and a feral population. Based on mapping information, the polymorphic site was determined to be in the ATPase 6 gene. Primers TK-J-3804 and C3-N-5460 amplified this region. The amplicon was cut by HaeIII in flies of one haplotype and not cut in flies of the other haplotype. From 30 to 43% of the individual flies studied had this additional HaeIlI site. After cloning of the approximately 5200 bp XbaI fragment, the two mitotypes were identified. A 988 base fragment, coding for the entire tRNA-Lys(AAG), tRNA-Asp(GAC), and ATPase 8genes, and a partial ATPase 6gene was sequenced Four silent mutations, including the one at the informative site were located. The HaeIII polymorphism and other sequence differences may prove useful as a diagnostic for identification of the origin of introduced fruit flies.

Animals↗
PubMed2002

Current strategies of antibody-based treatment in Hodgkin's disease.

Many new approaches involving antibody-based agents have given promising results in experimental Hodgkin's disease (HD) models. Clinical trials with monoclonal antibodies, immunotoxins, bispecific constructs and radioimmunoconjugates have demonstrated some clinical efficacy in patients with advanced refractory HD. Although it seems unlikely that resistant patients with larger tumor masses will be cured by either of these approaches, it might be feasible to treat bulky disease by conventional therapy and then administer biological agents to kill residual Hodgkin and Reed-Sternberg cells. Future phase III trials will have to prove a possible superior effect of this combined immunochemotherapy. Currently, the evaluation of the most promising approaches continues.

Antibodies, Monoclonal↗
PubMed2002

Visual event related potentials. The origin of wave P300. A computer model.

This five-layered model consisting of 180 neurons is aimed at simulating some elementary functions of primary visual cortex of mammals in form detection. Its main achievements are: 1. Detection of points, lines, simple geometric figures in the V1. 2. Abstraction of 19 different qualities of geometric figures. 3. Simulation and rational explanation of processing of peripheral stimuli in the V1, explanation of mechanism of origin of visual ERPs, including P300 wave. 4. Simulation and explanation of the nature and build up of the cognitive function within V1 and its possible relation to long-term memory. 5. The model is based partly on Hebb-type synapses, illustrates the role of neuronal assemblies, sheds light on the functional relationship of excitatory and inhibitory neurons, in their conformity with special tasks of different cortical layers.

Computer Simulation↗
PubMed2001

Ribosomes with large synthetic N-terminal extensions of protein S15 are active in vivo.

The genes for ribosomal proteins S4, S13 or S15 were fused with the gene for staphylococcal protein A, or derivatives thereof (2A'-7A'). The gene fusions were introduced into Escherichia coli strains, mutated in the corresponding ribosomal protein gene, by transformation. These mutated ribosomal proteins cause a phenotype that can be complemented. Thus, the phenotype of the transformants was tested and the ribosomal proteins were analyzed. The S4 N-terminal fusion protein severely disturbed growth of both the mutant and the wild-type strains. The S13 C-terminal fusion protein was proteolyzed close to the fusion point, giving a ribosomal protein moiety that could assemble into the ribosome normally. S15 N-terminal fusion proteins complemented a cold-sensitive strain lacking protein S15 in its ribosomes. These fused proteins were assembled into active ribosomes. The position of S15 in the 30S ribosomal subunit is well known. Therefore, in structural studies of the ribosome in vivo, the S15 fusion proteins can be used as a physical reporter for S15.

Base Sequence↗
PubMed2001

Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin's lymphoma.

BACKGROUND: BBR 2778 is a novel aza-anthracenedione showing no cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in animal models. Objectives of this phase I study included the determination of the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), clinical pharmacokinetics (PK), and antitumor activity. Patients with relapsed or refractory, advanced non-Hodgkin's lymphoma were included. PATIENTS AND METHODS: Patients were treated with a q1w x 3 schedule on the basis of a modified Fibonacci dose escalation method. Seven groups with a total of twenty-six patients were treated at dosages of 5, 10, 16.5, 25, 34, 56 or 84 mg/m2/w, respectively. RESULTS: DLT was observed on the seventh dose level with neutropenia WHO grade 4 in three of six patients. Pharmacokinetic analysis showed a large volume of distribution (13.5-17.5 l/kg), a high plasma clearance (0.65-1.74 l/h/kg) and a long elimination half-life (14.7-31.9 h). Tumor response included three complete remissions and two partial remissions. CONCLUSIONS: Neutropenia is the DLT of the new aza-anthracenedione BBR 2778. The recommend dose is 84 mg/m2 in a q1w x 3 schedule. PK data are consistent with a linear kinetic of BBR 2778 comparable to mitoxantrone. This new drug shows promising activity in intensively pretreated patients with relapsed or refractory NHL. Based on this results, phase II studies with this new compound are underway.

Adult↗
PubMed2000

Ki-4(scFv)-ETA', a new recombinant anti-CD30 immunotoxin with highly specific cytotoxic activity against disseminated Hodgkin tumors in SCID mice.

The human lymphocyte activation marker CD30 is highly overexpressed on Hodgkin/Reed-Sternberg cells and represents an ideal target for selective immunotherapy. We used the murine anti-CD30 hybridoma Ki-4 to construct a new recombinant immunotoxin (rIT) for possible clinical use in patients with CD30(+) lymphoma. Hybridoma V genes were polymerase chain reaction-amplified, assembled, cloned, and expressed as a mini-library for display on filamentous phage. Functional Ki-4 scFv obtained by selection of binding phage on the CD30-expressing Hodgkin lymphoma cell line L540cy was inserted into the bacterial expression vector pBM1.1 and fused to a deletion mutant of Pseudomonas exotoxin A (ETA'). Periplasmically expressed Ki-4(scFv)-ETA' demonstrated specific activity against a variety of CD30(+) lymphoma cells as assessed by different in vitro assays. To evaluate in vivo antitumor activity, severe combined immunodeficient mice challenged with human lymphoma cell lines were treated with the immunotoxin. The blood distribution time t(1/2)alpha of Ki-4(scFv)-ETA' was 19 minutes, and its serum elimination time t(1/2)alpha was 193 minutes. A single intravenous injection of 40 microg rIT 1 day after tumor inoculation rendered 90% of the mice tumor free, extending the mean survival time to more than 200 days compared with 38.1 days in the phosphate-buffered saline control group (P <.001). This new rIT is a promising candidate for further clinical evaluation in patients with Hodgkin lymphoma or other CD30(+) malignancies. (Blood. 2000;95:3909-3914)

Animals↗
PubMed2000

Recombinant anti-CD25 immunotoxin RFT5(SCFV)-ETA' demonstrates successful elimination of disseminated human Hodgkin lymphoma in SCID mice.

Since clinical phase-I/II trials in patients with resistant Hodgkin's lymphoma treated with the chemically linked anti-CD25 ricin-A-chain immunotoxin RFT5-SMPT-dgA indicate promising results for patients with minimal residual disease, we constructed a new immunotoxin by fusing the RFT5 single-chain variable fragment to a deletion mutant of Pseudomonas exotoxin A (ETA'). The recombinant protein was directed into the periplasmic space of E. coli by means of the pET-derived expression vector pBM1.1 and our newly developed expression/purification method. Biologically active RFT5(scFv)-ETA' was isolated by freezing/thawing and purified by immobilized metal-ion affinity and molecular-size-chromatography. RFT5(scFv)-ETA' was subsequently used for the treatment of disseminated human Hodgkin's lymphoma in a SCID-mouse model. The mean survival time (MST) of L540rec-challenged SCID mice was 38.1 days. A single i.v. injection of 40 microg recombinant immunotoxin (rIT) 1 day after tumor inoculation resulted in 100% tumor-free mice, extending the MST to more than 220 days (p < 0.0001). The blood-distribution time T(1/2)alpha was 39.65 min, the serum elimination time T(1/2)alpha, 756.6 min. All animals were assessed for soluble interleukin-2 receptor alpha, which is directly correlated to tumor burden. Soluble CD25 was not detectable in mice treated with the rIT. Our findings, concerning potent anti-tumor effects of a recombinant anti-CD25 immunotoxin against disseminated Hodgkin's lymphoma in SCID mice reported here demonstrate that RFT5(scFv)-ETA' might be suitable for further evaluation against Hodgkin's lymphoma in humans.

Animals↗
PubMed2000

Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin.

The anti-CD25 immunotoxin RFT5.dgA was constructed by coupling the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin A-chain and was administered to patients with relapsed Hodgkin's lymphoma in four bolus infusions over 7 days (day 1, 3, 5 and 7). The maximum tolerated dose in these patients as defined in a previous phase I study was 15 mg/m2. Subsequently, further patients were enrolled at the maximum tolerated dose and a total of 18 patients were treated at this level. All patients had signs of progressive disease and were heavily pretreated. Side-effects in this trial were moderate and related to vascular leak syndrome. Five of 18 patients experienced NCI grade III toxicities including weakness, edema, dyspnea, and myalgia. Eleven of 16 (69%) patients receiving two or more cycles produced human anti-ricin antibodies and human anti-mouse antibodies (>/=1.0 microg/ml). Seventeen of 18 patients were evaluable for clinical response. These included two partial remissions. One patient demonstrated minor response and five patients stable diseases. We conclude that RFT5.dgA is of moderate clinical efficacy in this group of heavily pretreated refractory patients. Leukemia (2000) 14, 129-135.

Hodgkin Disease↗