Showing papers by "University of Erlangen-Nuremberg published in 1999"

Vaccination with Mage-3a1 Peptide–Pulsed Mature, Monocyte-Derived Dendritic Cells Expands Specific Cytotoxic T Cells and Induces Regression of Some Metastases in Advanced Stage IV Melanoma

Abstract: Dendritic cells (DCs) are considered to be promising adjuvants for inducing immunity to cancer. We used mature, monocyte-derived DCs to elicit resistance to malignant melanoma. The DCs were pulsed with Mage-3A1 tumor peptide and a recall antigen, tetanus toxoid or tuberculin. 11 far advanced stage IV melanoma patients, who were progressive despite standard chemotherapy, received five DC vaccinations at 14-d intervals. The first three vaccinations were administered into the skin, 3 × 106 DCs each subcutaneously and intradermally, followed by two intravenous injections of 6 × 106 and 12 × 106 DCs, respectively. Only minor (less than or equal to grade II) side effects were observed. Immunity to the recall antigen was boosted. Significant expansions of Mage-3A1–specific CD8+ cytotoxic T lymphocyte (CTL) precursors were induced in 8/11 patients. Curiously, these immune responses often declined after the intravenous vaccinations. Regressions of individual metastases (skin, lymph node, lung, and liver) were evident in 6/11 patients. Resolution of skin metastases in two of the patients was accompanied by erythema and CD8+ T cell infiltration, whereas nonregressing lesions lacked CD8+ T cells as well as Mage-3 mRNA expression. This study proves the principle that DC “vaccines” can frequently expand tumor-specific CTLs and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8+ CTL–tumor cell interaction in situ as well as escape by lack of tumor antigen expression.

Multilevel codes: theoretical concepts and practical design rules

Abstract: This paper deals with 2/sup l/-ary transmission using multilevel coding (MLC) and multistage decoding (MSD). The known result that MLC and MSD suffice to approach capacity if the rates at each level are appropriately chosen is reviewed. Using multiuser information theory, it is shown that there is a large space of rate combinations such that MLC and full maximum-likelihood decoding (MLD) can approach capacity. It is noted that multilevel codes designed according to the traditional balanced distance rule tend to fall in the latter category and, therefore, require the huge complexity of MLD. The capacity rule, the balanced distances rules, and two other rules based on the random coding exponent and cutoff rate are compared and contrasted for practical design. Simulation results using multilevel binary turbo codes show that capacity can in fact be closely approached at high bandwidth efficiencies. Moreover, topics relevant in practical applications such as signal set labeling, dimensionality of the constituent constellation, and hard-decision decoding are emphasized. Bit interleaved coded modulation, proposed by Caire et al. (see ibid., vol.44, p.927-46, 1998), is reviewed in the context of MLC. Finally, the combination of signal shaping and coding is discussed. Significant shaping gains are achievable in practice only if these design rules are taken into account.

Stochastic stability of the discrete-time extended Kalman filter

Abstract: The authors analyze the error behavior for the discrete-time extended Kalman filter for general nonlinear systems in a stochastic framework. In particular, it is shown that the estimation error remains bounded if the system satisfies the nonlinear observability rank condition and the initial estimation error as well as the disturbing noise terms are small enough. This result is verified by numerical simulations for an example system.

Valacyclovir for the Prevention of Cytomegalovirus Disease after Renal Transplantation

Abstract: Background Cytomegalovirus (CMV) disease is a major complication of organ transplantation. We hypothesized that prophylactic treatment with valacyclovir would reduce the risk of CMV disease. Methods A total of 208 CMV-negative recipients of a kidney from a seropositive donor and 408 CMV-positive recipients were randomly assigned to receive either 2 g of valacyclovir or placebo orally four times daily for 90 days after transplantation, with the dose adjusted according to renal function. The primary end point was laboratory-confirmed CMV disease in the first six months after transplantation. Results Treatment with valacyclovir reduced the incidence or delayed the onset of CMV disease in both the seronegative patients (P<0.001) and the seropositive patients (P=0.03). Among the seronegative patients, the incidence of CMV disease 90 days after transplantation was 45 percent among placebo recipients and 3 percent among valacyclovir recipients. Among the seropositive patients, the respective values were 6 percent and 0 percent. At six months, the incidence of CMV disease was 45 percent among seronegative recipients of placebo and 16 percent among seronegative recipients of valacyclovir; it was 6 percent among seropositive placebo recipients and 1 percent among seropositive valacyclovir recipients. At six months, the rate of biopsy-confirmed acute graft rejection in the seronegative group was 52 percent among placebo recipients and 26 percent among valacyclovir recipients (P=0.001). Treatment with valacyclovir also decreased the rates of CMV viremia and viruria, herpes simplex virus disease, and the use of inpatient medical resources. Hallucinations and confusion were more common with valacyclovir treatment, but these events were not severe or treatment limiting. The rates of other adverse events were similar among the groups. Conclusions Prophylactic treatment with valacyclovir is a safe and effective way to prevent CMV disease after renal transplantation. (N Engl J Med 1999; 340:1462-70.) (C) 1999, Massachusetts Medical Society.

β-Catenin Regulates the Expression of the Matrix Metalloproteinase-7 in Human Colorectal Cancer

Abstract: Most colorectal cancers have loss of function mutations in the adenomatosis polyposis coli (APC) tumor suppressor gene. This leads to accumulation of β-catenin, which together with the DNA binding protein TCF-4 functions as a transcriptional activator. Recently defined target genes are c-myc and cyclin D1, linking the APC gene defect to the capacity for autonomous proliferation of colon tumors. Here we report the identification of the matrix metalloproteinase MMP-7 as another target gene of β-catenin/TCF-4. MMP-7 is overexpressed in 80% of human colorectal cancers and known to be an important factor for early tumor growth, with a potential function also for later progression steps, like invasion and metastasis. Our results explain the high percentage of MMP-7 overexpression in colon tumors. Moreover they indicate that defects in the APC tumor suppressor gene may also have an influence on later steps of colon tumor progression.

Surgical treatment of craniopharyngiomas: experience with 168 patients

Abstract: Object. The goal of this study was to assess the outcome of surgical management in 168 consecutive patients harboring craniopharyngiomas treated between January 1983 and April 1997. Methods. In 148 patients undergoing initial (primary) surgery, the pterional approach was most frequently used (39.2%), followed by the transsphenoidal approach (23.6%). For large retrochiasmatic craniopharyngiomas, the bifrontal interhemispheric approach was used increasingly over the pterional approach and led to improved surgical results. Total tumor removal was accomplished in 45.7% of transcranial and 85.7% of transsphenoidal procedures. The main reasons for incomplete removal were attachment to and/or infiltration of the hypothalamus, major calcifications, and attachment to vascular structures. The success rate in total tumor removal was inferior in the cases of tumor recurrence. The operative mortality rate in transcranial surgery was 1.1% in primary cases and 10.5% in cases of tumor recurrence. No patient died in the group that underwent transsphenoidal surgery. The rate of recurrence-free survival after total removal was 86.9% at 5 years and 81.3% at 10 years. In contrast, the 5-year recurrence-free survival rate was only 48.8% after subtotal removal and 41.5% after partial removal. Following primary surgery, the actuarial survival rate was 92.7% at 10 years, with the best results after complete tumor removal. At last follow up, 117 (79%) of 148 patients who underwent primary surgery were independent and without impairment. Conclusions. Total tumor removal while avoiding hazardous intraoperative manipulation provides favorable early results and a high rate of long-term control in craniopharyngiomas.

Cell-to-Cell and Long-Distance Trafficking of the Green Fluorescent Protein in the Phloem and Symplastic Unloading of the Protein into Sink Tissues

Abstract: Macromolecular trafficking within the sieve element-companion cell complex, phloem unloading, and post-phloem transport were studied using the jellyfish green fluorescent protein (GFP). The GFP gene was expressed in Arabidopsis and tobacco under the control of the AtSUC2 promoter. In wild-type Arabidopsis plants, this promoter regulates expression of the companion cell-specific AtSUC2 sucrose-H+ symporter gene. Analyses of the AtSUC2 promoter-GFP plants demonstrated that the 27-kD GFP protein can traffic through plasmodesmata from companion cells into sieve elements and migrate within the phloem. With the stream of assimilates, the GFP is partitioned between different sinks, such as petals, root tips, anthers, funiculi, or young rosette leaves. Eventually, the GFP can be unloaded symplastically from the phloem into sink tissues, such as the seed coat, the anther connective tissue, cells of the root tip, and sink leaf mesophyll cells. In all of these tissues, the GFP can traffic cell to cell by symplastic post-phloem transport. The presented data show that plasmodesmata of the sieve element-companion cell complex, as well as plasmodesmata into and within the analyzed sinks, allow trafficking of the 27-kD nonphloem GFP protein. The data also show that the size exclusion limit of plasmodesmata can change during organ development. The results are also discussed in terms of the phloem mobility of assimilates and of small, low molecular weight companion cell proteins.

International Union Against Cancer. Classification of isolated tumor cells and micrometastasis.

Abstract: Background Findings of isolated (disseminated or circulating) tumor cells (ITC) by immunocytochemistry and molecular pathology methods have led to varied interpretations and different applications of the TNM system. Methods An analysis of the relevant literature was undertaken. In addition, optional proposals for the classification of ITC, micrometastasis, and cytologic results in pleural and peritoneal washings are presented. Results Immunocytochemistry has a lower false-positive rate than nonmorphologic methods such as flow cytometry or the polymerase chain reaction; therefore the method(s) used always should be recorded. At the current time, the independent prognostic significance of ITC in regional lymph nodes and in the general circulation (blood, bone marrow, and other distant sites) is difficult to assess. To enable comparisons of treatment results and to avoid variation in staging, a finding of ITC should not be considered in the TNM and residual tumor (R) classifications, at least not at the current time. However, for future evaluation of their prognostic significance, the respective findings should be documented according to uniform criteria. Conclusions ITC should be distinguished from micrometastasis. To investigate the independent prognostic significance of ITC and of positive lavage cytology, uniform data collection according to the proposed coding schema is recommended.

Long-term memory motion-compensated prediction

Abstract: Long-term memory motion-compensated prediction extends the spatial displacement vector utilized in block-based hybrid video coding by a variable time delay permitting the use of more frames than the previously decoded one for motion compensated prediction. The long-term memory covers several seconds of decoded frames at the encoder and decoder. The use of multiple frames for motion compensation in most cases provides significantly improved prediction gain. The variable time delay has to be transmitted as side information requiring an additional bit rate which may be prohibitive when the size of the long-term memory becomes too large. Therefore, me control the bit rate of the motion information by employing rate constrained motion estimation. Simulation results are obtained by integrating long-term memory prediction into an H.263 codec. Reconstruction PSNR improvements up to 2 dB for the Foreman sequence and 1.5 dB for the Mother-Daughter sequence are demonstrated in comparison to the TMN-2.0 H.263 coder. The PSNR improvements correspond to bit-rate savings up to 34 and 30%, respectively. Mathematical inequalities are used to speed up motion estimation while achieving full prediction gain.

Inhalation of nitric oxide in acute lung injury: results of a European multicentre study

Abstract: Objective: To determine whether inhalation of nitric oxide (INO) can increase the frequency of reversal of acute lung injury (ALI) in nitric oxide (NO) responders Design: Prospective, open, randomised, multicentre, parallel group phase III trial Setting: General ICUs in 43 university and regional hospitals in Europe Patients: Two hundred and sixty-eight adult patients with early ALI Interventions: NO responders were patients whose PaO2 increased by more than 20 % when receiving 0, 2, 10 and 40 ppm of INO for 10 min within 96 h of study entry Responders were randomly allocated to conventional treatment with or without INO INO, 1–40 ppm, was given at the lowest effective dose for up to 30 days or until an end point was reached The primary end point was reversal of ALI Clinical outcome parameters and safety were assessed in all patients Results: Two hundred and sixty-eight patients were recruited, of which 180 were randomised NO responders Frequency of reversal of ALI was no different in INO patients (61 %) and controls (54 %; p > 02) Development of severe respiratory failure was lower in the INO (22 % ) than controls (103 %; p 02 vs INO) and 45 % in non-responders Conclusions: Improvement of oxygenation by INO did not increase the frequency of reversal of ALI Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia

Shell structure of superheavy nuclei in self-consistent mean-field models

Abstract: We study the extrapolation of nuclear shell structure to the region of superheavy nuclei in self-consistent mean-field models[emdash]the Skyrme-Hartree-Fock approach and the relativistic mean-field model[emdash]using a large number of parametrizations which give similar results for stable nuclei but differ in detail. Results obtained with the folded-Yukawa potential which is widely used in macroscopic-macroscopic models are shown for comparison. We focus on differences in the isospin dependence of the spin-orbit interaction and the effective mass between the models and their influence on single-particle spectra. The predictive power of the mean-field models concerning single-particle spectra is discussed for the examples of [sup 208]Pb and the spin-orbit splittings of selected neutron and proton levels in [sup 16]O, [sup 132]Sn, and [sup 208]Pb. While all relativistic models give a reasonable description of spin-orbit splittings, all Skyrme interactions show a wrong trend with mass number. The spin-orbit splitting of heavy nuclei might be overestimated by 40[percent][endash]80[percent], which exposes a fundamental deficiency of the current nonrelativistic models. In most cases the occurrence of spherical shell closures is found to be nucleon-number dependent. Spherical doubly magic superheavy nuclei are found at [sub 184][sup 298]114, [sub 172][sup 292]120, or [sub 184][sup 310]126 depending on the parametrization. The Z=114more » proton shell closure, which is related to a large spin-orbit splitting of proton 2f states, is predicted only by forces which by far overestimate the proton spin-orbit splitting in [sup 208]Pb. The Z=120 and N=172 shell closures predicted by the relativistic models and some Skyrme interactions are found to be related to a central depression of the nuclear density distribution. This effect cannot appear in macroscopic-microscopic models or semiclassical approaches like the extended Thomas-Fermi-Strutinski integral approach which have a limited freedom for the density distribution only. In summary, our findings give a strong argument for [sub 172][sup 292]120 to be the next spherical doubly magic superheavy nucleus. [copyright] [ital 1999] [ital The American Physical Society]« less

Dose reduction in CT by anatomically adapted tube current modulation. II. Phantom measurements

Abstract: Theoretical considerations and simulation studies have led to the expectation that patient dose in CT(computed tomography) can be reduced significantly without a concomitant loss in image quality if tube current is modulated according to rotation angle-dependent x-ray attenuation. In this study, the simulation results presented in Part I were validated with phantoms. We used one cylindrical, two oval, and one elliptical phantom, available both as mathematical descriptions and in physical form, to mimic different parts of the human anatomy. Prototype hardware was available to control tube current on a commercial clinical CT scanner. The potential for dose reduction was evaluated for sinusoidal and attenuation-based current modulation for variable modulation amplitudes. Agreement between simulations and measured results was better than within 10%. Dose reduction values of 8%–56% were found depending on the phantom geometry and tube current modulation function. Attenuation-based tube current modulation consistently yielded higher reduction than fixed-shape sinusoidal modulation functions. For the shoulder phantom and 70% modulation amplitude, 44.6% dose reduction was measured as compared to 34.1% for sinusoidal modulation. A maximum of 56% was measured for the shoulder phantom including inserts. Specifying mAs reduction as an estimate for dose reduction proved to be a valid and conservative estimate; measured dose is reduced more strongly than the total mAs product both centrally and on average. First patient studies confirm the results of simulation and phantom studies. We conclude that attenuation-based online tube current control has great potential for reducing patient dose in CT and that it should be made generally available for clinical use.

Dose reduction in CT by anatomically adapted tube current modulation. I. Simulation studies.

Abstract: The physical principles of dose reduction in computed tomography (CT) by anatomy-oriented attenuation-based tube current modulation, as discussed elsewhere in this volume (see Chap. 4), were tested in a first clinical patient study. Our aim was to reduce the dose applied in CT by current modulation and without a loss of image quality. Dose reduction was measured by the reduction of the mAs product, and image quality was assessed subjectively by experienced radiologists.

The end of the road for silicon

Abstract: Computer chips continue to shrink. But the discovery that a layer of silicon dioxide must be at least four to five atoms thick to function as an insulator suggests that silicon-based microchips will reach the physical limits of miniaturization early next century.

Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose

Abstract: Cyclic ADP-ribose (cADPR) is a natural compound that mobilizes calcium ions in several eukaryotic cells1,2,3. Although it can lead to the release of calcium ions in T lymphocytes4,5,6,7, it has not been firmly established as a second messenger in these cells. Here, using high-performance liquid chromatography analysis8, we show that stimulation of the T-cell receptor/CD3 (TCR/CD3) complex results in activation of a soluble ADP-ribosyl cyclase and a sustained increase in intracellular levels of cADPR. There is a causal relation between increased cADPR concentrations, sustained calcium signalling and activation of T cells, as shown by inhibition of TCR/CD3-stimulated calcium signalling, cell proliferation and expression of the early- and late-activation markers CD25 and HLA-DR by using cADPR antagonists9. The molecular target for cADPR, the type-3 ryanodine receptor/calcium channel, is expressed in T cells. Increased cADPR significantly and specifically stimulates the apparent association of [3H]ryanodine with the type-3 ryanodine receptor, indicating a direct modulatory effect of cADPR on channel opening. Thus we show the presence, causal relation and biological significance of the major constituents of the cADPR/calcium-signalling pathway in human T cells.

Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS

Abstract: The relation of procalcitonin (PCT) plasma concentrations comparedwith C-reactive protein (CRP) was analyzed in patients with different severityof multiple organ dysfunction syndrome (MODS) and systemic inflammation. PCT, CRP, the sepsis-related organ failure assessment (SOFA)score, the Acute Physiology, Age, Chronic Health Evaluation (APACHE) II scoreand survival were evaluated in 40 patients with systemic inflammation andconsecutive MODS over a period of 15 days. Higher SOFA score levels were associated with significantly higherPCT plasma concentrations (SOFA 7-12: PCT 2.62 ng/ml, SOFA 19-24: PCT15.22 ng/ml) (median), whereas CRP was elevated irrespective of the scoresobserved (SOFT 7-12: CRP 131 mg/l, SOFT 19-24: CRP 135 mg/l). PCT ofnon-surviving patients was initially not different from that of survivors butsignificantly increased after the fourth day following onset of the disease,whereas CRP was not different between both groups throughout the wholeobservation period. Measurement of PCT concentrations during multiple organdysfunction syndrome provides more information about the severity and thecourse of the disease than that of CRP. Regarding the strong association of PCTand the respective score systems in future studies we recommend evaluation alsoof the severity of inflammation and MODS when PCT concentrations were comparedbetween different types of disease.

Biochemical taxonomy and molecular phylogeny of the genus chlorella sensu lato (chlorophyta)

Abstract: A multimethod approach was used to characterize unicellular green algae that were traditionally assigned to the genus Chlorella Beijerinck and to resolve their phylogenetic relationships within the Chlorophyta. Biochemical, physiological, and ultrastructural characters, together with molecular data such as DNA base composition and DNA hybridization values, were compared with a molecular phylogeny based on complete 18S rRNA sequences. Our results show that Chlorella taxa are dispersed over two classes of chlorophytes, the Trebouxiophyceae and the Chlorophyceae. We propose that only four species should be kept in the genus Chlorella (Chlorophyta, Trebouxiophyceae): C. vulgaris Beijerinck, C. lobophora Andreyeva, C. sorokiniana Shih. et %

Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases.

Abstract: Background: Angiotensin II (ANG II) mediated hypertension accelerates atherosclerosis (AS) and thereby increases the incidence of myocardial infarction (MI). On the other hand, superoxide anion (O2−) is involved in the modification of low density lipoproteins, inhibition of prostacyclin (PGI2) formation and breakdown of nitric oxide. These events finally lead to rapid progression of AS and MI. In the present study, we investigate whether ANG II can induce O2− release from human vascular endothelial cells (HVECs) and the possible mechanisms involved. Methods and Results: The expression of ANG receptors subtype-1 (AT-1) and subtype-2 (AT-2) were identified by using reverse transcription polymerase chain reaction and sequence analysis. The O2− production was dose-dependently increased in HVECs treated with ANG II (10−7–10−9 M) and with a maximum rate after 1 h of incubation. This event was significantly inhibited by pretreatment of cells with the specific AT-1 blocker losartan (10−7 M) and to a lesser extent by the specific AT-2 receptor blocker PD123319 (10−7 M). The combined incubation of both receptor blockers was even more effective. In addition, our lucigenin-enhanced chemiluminescence assay showed that the activity of plasma membrane-bound NADH-/NADPH-oxidases derived from ANG II-treated cells was also significantly increased, this effect was reduced in cells pretreated with losartan or to lesser extent by PD123319. However, the activity of xanthine oxidase remained unchanged in response to ANG II. Furthermore, the basal O2− release from HVECs was inhibited in cells treated with angiotensin-converting enzyme (ACE) inhibitor, Lisinopril (10−6 M), and this event could be reversed by ANG II. Conclusion: ANG II induces O2− release in HVECs via activation of membrane-bound NADH-/NADPH-oxidases, an effect, that is mediated by both AT-1 and AT-2 receptors. This suggests that acceleration of AS and MI in ANG II-mediated hypertension may at least be due to ANG II-induced O2− generation from vascular endothelial cells. In this case, the ACE inhibitors and the ANG receptor antagonists may act as causative “antioxidants”.

Spread spectrum watermarking: malicious attacks and counterattacks

Abstract: Most watermarking methods for images and video have been proposed are based on ideas from spread spectrum radio communications, namely additive embedding of a (signal adaptive or non-adaptive) pseudo-noise watermark pattern, and watermark recovery by correlation. Even methods that are not presented as spread spectrum methods often build on these principles. Recently, some skepticism about the robustness of spread spectrum watermarks has arisen, specifically with the general availability of watermark attack software which claim to render most watermarks undetectable. In fact, spread spectrum watermarks and watermark detectors in their simplest form are vulnerable to a variety of attacks. However, with appropriate modifications to the embedding and extraction methods, spread spectrum methods can be made much more resistant against such attacks. In this paper, we review proposed attacks on spread spectrum watermarks are systematically. Further, modifications for watermark embedding and extraction are presented to avoid and counterattack these attacks. Important ingredients are, for example, to adapt the power spectrum of the watermark to the host signal power spectrum, and to employ an intelligent watermark detector with a block-wise multi-dimensional sliding correlator, which can recover the watermark even in the presence of geometric attacks.

Robust Internet video transmission based on scalable coding and unequal error protection

Abstract: In this article we describe and investigate an Internet video streaming system based on a scalable video coder combined with unequal error protection that maintains an acceptable picture quality over a wide range of connection qualities. The proposed approach does not require any specific support from the network layer and is especially suited for Internet multicast applications where different users are perceiving different transmission conditions and no feedback channel can be employed. We derive a theoretical framework for the overall system by which the Internet packet loss behavior can be directly related to the picture quality perceived at the receiver. We demonstrate how this framework can be used to select appropriate parameter values for the overall system design. Experimental results show how the presented system achieves a gracefully degrading picture quality for packet losses up to 30%.

Nitric oxide (NO): an effector of apoptosis.

Abstract: It is appreciated that the production of nitric oxide (NO) from L-arginine metabolism is an essential determinate of the innate immune system, important for nonspecific host defense, as well as tumor and pathogen killing. Cytotoxicity as a result of a substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro- and anti-apoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, chromatin condensation, and DNA fragmentation. Proof for the involvement of NO was demonstrated by blocking adverse effects by NO-synthase inhibition. However, NO-toxicity is not a constant value and NO may achieve cell protection as well. In part this is understood by transcription and translation of protective proteins, such as cyclooxygenase-2. Alternatively, protection may result as a consequence of a diffusion controlled NO/O2− (superoxide) interaction that redirects the apoptotic initiating activity of NO towards protection. NO is endowed with the unique ability to initiate and to block apoptosis, depending on multiple variables that exist to be elucidated. The crosstalk between cell destructive and protective signaling pathways under the modulatory influence of NO will determine the impact of NO in apoptotic cell death and survival.