Biomedical subjects

Volker Kunzmann

Publications and source records attributed to Volker Kunzmann.

12 recordsLinked to original sources

PubMed2006

The Berlin Brain-Computer Interface: EEG-based communication without subject training.

The Berlin Brain-Computer Interface (BBCI) project develops a noninvasive BCI system whose key features are 1) the use of well-established motor competences as control paradigms, 2) high-dimensional features from 128-channel electroencephalogram (EEG), and 3) advanced machine learning techniques. As reported earlier, our experiments demonstrate that very high information transfer rates can be achieved using the readiness potential (RP) when predicting the laterality of upcoming left- versus right-hand movements in healthy subjects. A more recent study showed that the RP similarily accompanies phantom movements in arm amputees, but the signal strength decreases with longer loss of the limb. In a complementary approach, oscillatory features are used to discriminate imagined movements (left hand versus right hand versus foot). In a recent feedback study with six healthy subjects with no or very little experience with BCI control, three subjects achieved an information transfer rate above 35 bits per minute (bpm), and further two subjects above 24 and 15 bpm, while one subject could not achieve any BCI control. These results are encouraging for an EEG-based BCI system in untrained subjects that is independent of peripheral nervous system activity and does not rely on evoked potentials even when compared to results with very well-trained subjects operating other BCI systems.

Algorithms↗

PubMed2005

Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin.

PURPOSE: As prognosis of advanced pancreatic cancer remains gloomy, novel therapeutic modalities have to be developed. Immunotherapy, which targets tumor-associated antigens of tumor cells or tumor stroma, is currently under investigation. As survivin is expressed by neoplastic and tumor endothelial cells, but rarely by normal cells, this antigen appears as an intriguing target molecule. METHODS: A 72-year old patient, suffering from pancreatic cancer refractory to gemcitabine therapy, received the survivin-based peptide vaccinations consisting of 100 mug of a modified HLA-A2 restricted survivin(96-104) epitope in Montanide(R). Each visit the patient was assessed for adverse events, quality of life and immunological response. Immuno-monitoring was performed by IFN-gamma-ELISPOT analysis of peripheral blood lymphocytes. Clinical outcome was evaluated by repetitive computed tomography. RESULTS: Under vaccination with survivin peptides the patient initially underwent partial remission of liver metastasis which proceeded after 6 months into a complete remission with a duration of 8 months. Immunological monitoring revealed strong vaccine-induced immune-reactivity against survivin. Unfortunately, after the patient was weaned from vaccination in state of no evidence of disease, he developed recurrent disease. CONCLUSION: T-cell responses against survivin-expressing cells of the tumor itself and tumor endothelium should impact tumor growth and metastasis. The presented patient with pancreatic cancer is the first example of a successful application of a survivin-based vaccination in the clinical setting. An ongoing phase I/II trial with HLA-A1, -A2 and -B35 restricted survivin peptides for patients with advanced cancer will provide further information towards this notion.

Adenocarcinoma↗

PubMed2005

Activation of V gamma 9V delta 2 T cells by NKG2D.

Human Vgamma9 Vdelta2 T cells recognize phosphorylated nonpeptide Ags (so called phosphoantigens), certain tumor cells, and cells treated with aminobisphosphonates. NKG2D, an activating receptor for NK cells, has been described as a potent costimulatory receptor in the Ag-specific activation of gammadelta and CD8 T cells. This study provides evidence that Vgamma9 Vdelta2 T cells may also be directly activated by NKG2D. Culture of PBMC with immobilized NKG2D-specific mAb or NKG2D ligand MHC class I related protein A (MICA) induces the up-regulation of CD69 and CD25 in NK and Vgamma9 Vdelta2 but not in CD8 T cells. Furthermore, NKG2D triggers the production of TNF-alpha but not of IFN-gamma, as well as the release of cytolytic granules by Vgamma9 Vdelta2 T cells. Purified Vgamma9 Vdelta2 T cells kill MICA-transfected RMA mouse cells but not control cells. Finally, DAP10, which mediates NKG2D signaling in human NK cells, was detected in resting and activated Vgamma9 Vdelta2 T cells. These remarkable similarities in NKG2D function in NK and Vgamma9 Vdelta2 T cells may open new perspectives for Vgamma9 Vdelta2 T cell-based immunotherapy, e.g., by Ag-independent killing of NKG2D ligand-expressing tumors.

Animals↗

PubMed2005

Anti-lymphoma effect of gammadelta T cells.

During the last few years, our knowledge about the activation and control of non-major histocompatibility complex (MHC)-restricted innate effector lymphocytes (such as natural killer (NK) cells, NK T cells and gammadelta T cells) has advanced enormously and immunotherapeutic strategies based on these cell types receive more and more attention. Apart from NK cells, several lines of evidence indicate that T cells, which express an alternative T cell receptor (TCR) composed of a CD3-associated gammadelta heterodimer, also contribute to the innate immune defense against tumors. Human gammadelta T cells represent a small subset of T cells (1-10% of peripheral blood T cells) and differ from conventional MHC-restricted ass T cells in recognition of a unique set of antigens ("phosphoantigens") and the lack of requirement of classical antigen-presenting molecules. Besides their role in the innate immune response against pathogens based on the recognition of distinctive microbial metabolic products (metabolites of the non-mevalonate pathway of isoprenoid synthesis), Vgamma9Vdelta2 T cells that constitute the dominant fraction of gammadelta T cells in humans exert potent cytotoxic activity, especially against lymphoid malignancies, mediated by as yet only partially determined pathway(s) of tumor recognition. This article will review available evidence from pre-clinical and early clinical studies regarding the contribution of gammadelta T cells in the defense against lymphoid malignancies and highlights some important issues that need to be addressed in the future.

Animals↗

PubMed2004

Myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation as first-line therapy in peripheral T-cell lymphomas: first results of a prospective multicenter study.

Peripheral T-cell lymphomas (PTCL) show a poor outcome following conventional chemotherapy. However, the role of high-dose therapy is still unclear. We initiated a prospective multicenter phase II study to evaluate the feasibility and the efficacy of myeloablative radiochemotherapy followed by autologous peripheral blood stem cell transplantation (APBSCT) as first-line treatment in PTCL. After 4-6 courses CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) chemotherapy, an induction therapy with either the DexaBEAM (dexamethasone, carmustine, melphalan, etoposide, and cytarabine) or the ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) protocol was administered. If a complete (CR) or a partial remission (PR) was achieved, myeloablative radiochemotherapy (hyperfractionated total body irradiation and high-dose cyclophosphamide) with APBSCT was performed. From June 2000 to November 2002, 30 patients (pts) were enrolled into the study. The two main PTCL subgroups included were PTCL not specified and angioimmunoblastic T-cell lymphoma (each n=12). In all, 21 of the 30 pts (70%) were transplanted. The main toxicities were myelosuppression and infections. The overall response rate after myeloablative therapy was 100% (20 CR, one PR). In total, 16 of 21 transplanted pts (76%) remained in CR at a median follow-up of 15 months (range, 6-32 months) from treatment start. Nine pts received no APBSCT mainly due to progressive disease. In conclusion, this first prospective PTCL-restricted study of frontline myeloablative radiochemotherapy with APBSCT shows feasibility and high efficacy. Our data suggest a substantial impact on outcome, however, longer follow-up is necessary to confirm survival benefit.

Adult↗

PubMed2004

Polyinosinic-polycytidylic acid-mediated stimulation of human gammadelta T cells via CD11c dendritic cell-derived type I interferons.

The recognition of pathogen-associated molecular patterns (PAMPs) by the innate immune system is a crucial step in inducing effective immune responses. Double-stranded RNA [mimicked by polyinosinic-polycytidylic acid (poly(I:C)], synthesized by various types of viruses, represents one important member of these immunostimulatory microbial components. Here we report that poly(I:C) has potent gammadelta T-cell costimulatory capacity. Within peripheral blood mononuclear cells, poly(I:C)-stimulated gammadelta T cells expressed increased levels of CD69 and exhibited significantly enhanced antigen-mediated proliferation in response to isopentenylpyrophosphate (IPP). Among several recombinant cytokines tested, type I interferons (IFN-alpha, IFN-beta) and interleukin-15 (IL-15) showed a similar activation pattern of gammadelta T cells. gammadelta T-cell clones and purified gammadelta T cells did not respond to poly(I:C), indicating indirect effects of this compound. Depletion of CD11c(+) dendritic cells (DC), which express Toll-like receptor 3 (TLR3), known to recognize poly(I:C), abrogated poly(I:C)-mediated stimulation of gammadelta T cells. In addition, the supernatant of poly(I:C)-treated CD11c(+) DC was able to mimic the stimulatory effects of poly(I:C) on gammadelta T cells. Experiments with neutralizing antibodies indicated that type I IFNs, but not IL-15, contributed to the poly(I:C)-mediated activation of gammadelta T cells. In conclusion, gammadelta T-cell activation by immunostimulatory double-stranded RNA, such as poly(I:C), is indirectly mediated via type I IFNs derived from TLR3-expressing CD11c(+) DCs. These results suggest that upon confrontation with certain viruses, gammadelta T cells can be rapidly activated by type I interferons and may contribute to effective antiviral responses.

Allergens↗

PubMed2003

Gammadelta T cells for immune therapy of patients with lymphoid malignancies.

There is increasing evidence that gammadelta T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent gammadelta T cell stimulatory compounds that induce cytokine secretion (ie, interferon gamma [IFN-gamma]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of gammadelta T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of gammadelta T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 x 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, gammadelta T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of gammadelta T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of gammadelta T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of gammadelta T cells responded to treatment, indicating that gammadelta T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that gammadelta T-cell-mediated immunotherapy is feasible and can induce objective tumor responses.

Adult↗

PubMed2003

Conditions of iodine contrast transfer from lumbosacral CSF to blood.

PURPOSE: To determine conditions which influence transfer of iopamidol from lumbosacral cerebrospinal fluid (CSF) to blood. METHODS: Iopamidol transfer was measured in 32 patients over 180 min after radiculography and compared with patient variables. RESULTS: Iopamidol transfer began early in 12 patients, more slowly in 13 patients, and was not detected during sample period in 7 patients. Transfer of sequential samples correlated highly with each other (r>0.8). Transfer was more pronounced in patients with prominent nerve root sleeves on radiculogram (p=0.006, t test), and correlated inversely with body weight (r=-0.4258), and with albumin CSF/serum quotient (r=-0.4702). CONCLUSION: Early iopamidol transfer probably indicates transfer through spinal arachnoid villi and granulations with CSF bulk flow. Prominent nerve root sleeves may facilitate access to transfer sites. No transfer during sample period suggests no such spinal transfer, possibly due to sparse access to or presence of spinal transfer sites. Inverse correlation of transfer with body weight may reflect influence of body weight on retroperitoneal venous pressure, which regulates outflow of CSF and of compounds dissolved in it. Awareness of wide interindividual transfer variation and steady intraindividual transfer may help to specify dosage and effect expectation of intrathecal drug therapy.

Adult↗

PubMed2003

Gene transfer in purified human hematopoietic peripheral-blood stem cells by means of electroporation without prestimulation.

Gene transfer in hematopoietic stem cells (HSCs) is an important tool, exploring regulation of the hematopoietic system and understanding the development and expansion of malignant cell clones. It is also a mandatory step for gene therapy of hematopoietic disorders. Although retroviral transduction of HSCs is effective, prestimulation of cells is generally required, also inducing differentiation of HSCs. Furthermore, the risk of viral recombination and insertional mutagenesis cannot be ruled out. Potential advantages of nonviral transfection are biosafety and easy management. However, experience in nonviral methods for transfecting peripheral-blood stem cells (PBSCs) is limited. To avoid differentiation, we evaluated the efficiency of gene transfer by means of electroporation without cytokine prestimulation. Compared with prestimulated (stem-cell factor, granulocyte-colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-6, erythropoietin, and monoclonal antibody to transforming growth factor-beta), transfection of thawed nonstimulated PBSCs was equally efficient, with a median transfection rate of 3.7%, transfection efficiency of 0.8%, and survival of 19.5% (n = 5). With freshly isolated HSCs, the rate of transfected cells could be increased to a median of 27.0% (range 8.3%-31.0%), transfection efficiency of 6.9% (range 4.5%-12.6%), and survival of 43% (range 22%-64%) (n = 5). However, the percentage of transfected cells declined with time; almost no cells were detectable by day 11. One cause for the lack of long-term expression of the heterologous gene in this system was induction of apoptosis in transgenic PBSCs, shown by up-regulation of CD95 (FAS antigen).

ADP-ribosyl Cyclase↗

PubMed2003

Boosting bit rates and error detection for the classification of fast-paced motor commands based on single-trial EEG analysis.

Brain-computer interfaces (BCIs) involve two coupled adapting systems--the human subject and the computer. In developing our BCI, our goal was to minimize the need for subject training and to impose the major learning load on the computer. To this end, we use behavioral paradigms that exploit single-trial EEG potentials preceding voluntary finger movements. Here, we report recent results on the basic physiology of such premovement event-related potentials (ERP). 1) We predict the laterality of imminent left- versus right-hand finger movements in a natural keyboard typing condition and demonstrate that a single-trial classification based on the lateralized Bereitschaftspotential (BP) achieves good accuracies even at a pace as fast as 2 taps/s. Results for four out of eight subjects reached a peak information transfer rate of more than 15 b/min; the four other subjects reached 6-10 b/min. 2) We detect cerebral error potentials from single false-response trials in a forced-choice task, reflecting the subject's recognition of an erroneous response. Based on a specifically tailored classification procedure that limits the rate of false positives at, e.g., 2%, the algorithm manages to detect 85% of error trials in seven out of eight subjects. Thus, concatenating a primary single-trial BP-paradigm involving finger classification feedback with such secondary error detection could serve as an efficient online confirmation/correction tool for improvement of bit rates in a future BCI setting. As the present variant of the Berlin BCI is designed to achieve fast classifications in normally behaving subjects, it opens a new perspective for assistance of action control in time-critical behavioral contexts; the potential transfer to paralyzed patients will require further study.

Algorithms↗

PubMed2002

Determinants of lumbar CSF protein concentration.

OBJECTIVE: To determine factors influencing the wide variation of protein concentration in lumbar cerebrospinal fluid (CSF). METHODS: Patient variables with potential influence on spinal CSF flow and resorption were measured in different patient settings and compared with albumin and IgG CSF/serum quotients. RESULTS: In patients whose diagnostic lumbar puncture produces normal CSF the albumin quotient increased with body mass index (r = 0.408), abdominal circumference (r = 0.399), and body weight (r = 0.317), age-corrected with partial correlation. Body motion before lumbar puncture showed only marginal influence on albumin quotient. In patients with radiculography the albumin quotient decreased with iodine contrast medium elimination from spinal subarachnoid space (r = -0.598) and increased with narrowing of lumbosacral spinal canal (r = 0.515). CONCLUSION: Correlation of albumin quotient with body mass index and related variables may be mediated by spinal CSF resorption, which should be impaired in overweight patients with elevated venous pressure. Negative correlation of albumin quotient with iodine resorption from spinal CSF supports this assumption. Correlation of albumin quotient with narrowing of lumbosacral canal should be due to slowed spinal CSF flow which does increase protein concentration. Tested variables explain part of variation of CSF protein concentration. Other variables like blood-CSF barrier permeability and pulsatile spinal CSF flow should have additional influence.

Adolescent↗

PubMed2001

Escherichia coli produces phosphoantigens activating human gamma delta T cells.

Human Vgamma9delta2 T lymphocytes are suggested to play an important role in the immune response to various microbial pathogens. In contrast to alphabeta T cells, gammadelta T lymphocytes recognize small, non-protein, phosphate-bearing antigens (phosphoantigens) in a major histocompatibility complex-independent manner. Four different phosphoantigens termed TUBag1 to TUBag4 with a common 3-formyl-1-butyl-pyrophosphate moiety and isopentenyl-pyrophosphate have been isolated and identified from mycobacteria. However, natural occurring gammadelta T cell ligands from other bacterial species were not characterized so far. Here, we describe the structural identification of the two compounds responsible for the gammadelta T cell-stimulating capacity of Escherichia coli as similar to the mycobacterial phosphoantigens 3-formyl-1-butyl-pyrophosphate and its M(r) 275 homologue TUBag2. In addition, E. coli phosphoantigens exert bioactivities on gammadelta T cells with similar potencies to the mycobacterial phosphoantigens at 5-15 nm concentration. Furthermore, our results clearly prove that the deoxyxylulose 5-phophate pathway (also referred to as Rohmer metabolic route of isoprenoid biosynthesis) is essential for the biosynthesis of the phosphoantigens in E. coli. Because this pathway is absent from human cells, it proves an ideal target for focusing efficiently the antimicrobial selectivity of human gammadelta T lymphocytes.

Antigens, Bacterial↗