Biomedical subjects

M Schroeder

Publications and source records attributed to M Schroeder.

At least 37 records · Page 2Linked to original sources

PubMed2002

[Medicinal therapy of malignant lymphomas].

Chemotherapy represents the most important therapeutic option in malignant lymphomas. Low to intermediate risk Hodgkin's disease is treated by a combination of chemotherapy and radiation. The new chemotherapy protocol BEACOPP has improved the outcome of advanced stages in comparison with the internationally accepted standard protocol COPP/ABVD. Dependent on the initial staging, cure rates between 50 and 95% can be achieved.Indolent non-Hodgkin's lymphomas usually present in advanced stages of disease. Chemotherapy in these cases has palliative character and aims at improving patients'quality of life and at avoiding complications due to the disease. In aggressive and very aggressive non-Hodgkin's lymphoma chemotherapy is curative and must be initiated immediately irrespective of the staging results. The efficacy of the standard protocol CHOP (cyclophosphamide,doxorubicin, vincristine and prednisone), that was established in the 1970s, has recently been improved by shortening of the therapy interval (CHOP-14 vs.CHOP-21),addition of etoposide (CHOEP) and combination with the monoclonal antibody rituximab (R-CHOP). The value of high dose chemotherapy with stem cell transplantation has been shown unequivocally only for aggressive non-Hodgkin lymphoma and relapsed Hodgkin's disease responsive to chemotherapy. The therapeutic strategy of malignant lymphomas is likely to be improved within the next years due to the introduction of novel cytostatic agents, the broadening application of monoclonal antibodies,upcoming new transplantation procedures and the development of substances with molecular targets. To rapidly increase our current knowledge on the topic it is mandatory to include patients into the large national and international multicenter studies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

A phase I study of oral uracil-ftorafur plus folinic acid in combination with weekly paclitaxel in patients with solid tumors.

INTRODUCTION: Ftorafur is an orally available prodrug of 5-fluorouracil (5-FU). Its combination with uracil in a molar ratio of 1:4 (UFT) increases the 5-FU concentration in tumor cells compared with ftorafur alone. Paclitaxel has a broad spectrum of activity against solid tumors and synergic effects with UFT have been demonstrated in vitro. A phase I study was performed to determine the maximum tolerated dose of the combination of UFT and paclitaxel in patients with advanced solid tumors. STUDY DESIGN: UFT and folinic acid were applied at 300 mg/m2/day and 90 mg/day, respectively, on days 1-28, repeated on day 36. Paclitaxel was applied on days 1, 8, 15 and 22 of each cycle. The starting dose of paclitaxel was 50 mg/m2 and escalation in 10 mg/m2 steps was performed up to 100 mg/m2 weekly. RESULTS: Forty-seven consecutive patients with various solid tumors have been included in six different dose levels. One hundred and thirty cycles have been applied. The treatment was well tolerated overall. Most frequently encountered adverse effects were gastrointestinal and hematological toxicity (diarrhea CTC 3/4 in 6% of patients, anemia in 11%, leukocytopenia in 9%, polyneuropathy in 9%, fatigue in 11%, other in 6%). Partial remissions were observed in 28% of patients. CONCLUSION: Owing to the lack of overlapping toxicities, UFT/folinic acid plus paclitaxel can be combined at doses of proven single agent activity. Side effects are mainly attributable to the gastrointestinal toxicity of UFT and to the neuro- and hematotoxicity of paclitaxel. The recommended doses for phase II studies are 300 mg/m2 of UFT plus 90 mg of folinic acid on days 1-28, and 90 mg/m2 of paclitaxel weekly.

Administration, Oral↗

PubMed2002

Phase II study of weekly paclitaxel plus 24-h continuous infusion 5-fluorouracil, folinic acid and 3-weekly cisplatin for the treatment of patients with advanced gastric cancer.

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2 shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.

Adenocarcinoma↗

PubMed2001

Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7.

To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7(-/-)). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7(-/-), but not in mGluR7(+/-), mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7(-/-) mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our findings suggest that mGluR7 receptors have a unique role in regulating neuronal excitability and that these receptors may be a novel target for the development of anticonvulsant drugs.

Animals↗

PubMed2001

Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation.

The Myc protein binds DNA and activates transcription by mechanisms that are still unclear. We used chromatin immunoprecipitation (ChIP) to evaluate Myc-dependent changes in histone acetylation at seven target loci. Upon serum stimulation of Rat1 fibroblasts, Myc associated with chromatin, histone H4 became locally hyperacetylated, and gene expression was induced. These responses were lost or severely impaired in Myc-deficient cells, but were restored by adenoviral delivery of Myc simultaneous with mitogenic stimulation. When targeted to chromatin in the absence of mitogens, Myc directly induced H4 acetylation. In addition, Myc recruited TRRAP to chromatin, consistent with a role for this cofactor in histone acetylation. Finally, unlike serum, Myc alone was very inefficient in inducing expression of most target genes. Myc therefore governs a step, most likely H4 acetylation, that is required but not sufficient for transcriptional activation. We propose that Myc acts as a permissive factor, allowing additional signals to activate target promoters.

Acetylation↗

PubMed2001

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer.

PURPOSE: To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). METHODS AND MATERIALS: Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). RESULTS: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072). CONCLUSION: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

Adult↗

PubMed2001

Saccharomyces Genome Database provides tools to survey gene expression and functional analysis data.

Upon the completion of the SACCHAROMYCES: cerevisiae genomic sequence in 1996 [Goffeau,A. et al. (1997) NATURE:, 387, 5], several creative and ambitious projects have been initiated to explore the functions of gene products or gene expression on a genome-wide scale. To help researchers take advantage of these projects, the SACCHAROMYCES: Genome Database (SGD) has created two new tools, Function Junction and Expression Connection. Together, the tools form a central resource for querying multiple large-scale analysis projects for data about individual genes. Function Junction provides information from diverse projects that shed light on the role a gene product plays in the cell, while Expression Connection delivers information produced by the ever-increasing number of microarray projects. WWW access to SGD is available at genome-www.stanford. edu/Saccharomyces/.

Databases, Factual↗

PubMed2001

Transradial approach for renal artery stenting.

Percutaneous interventional procedures in the renal arteries are usually performed using a femoral or brachial vascular access. The transradial approach, which has been extensively investigated for coronary angiography and intervention, could be an attractive new technique for renal artery angioplasty and stenting. In 18 patients with hemodynamically relevant unilateral renal artery stenosis (mean diameter stenosis, 83% +/- 18%; right, n = 7; left, n = 11), interventional treatment with PTA and stenting was performed using a left (n = 16) or right (n = 2) radial artery access. Indications for the transradial approach were acute aorto-renal angles or severe peripheral arterial obstructions. After engagement of the renal artery ostium with a 6 Fr Multipurpose guiding catheter (length, 125 cm; Cordis) the stenosis was passed with a 0.014" guidewire followed by stent implantation (ACS Multi-Link RX Ultra, Guidant; length, 18 mm; diameter, 5 mm). Direct stenting was successfully performed in 16 cases. Predilatations were required in two cases. In five patients, optimal stent expansion was achieved by additional postdilatations. A primary technical success (residual stenosis < 30%) could be achieved in all cases. There were no periprocedural complications. According to color-coded doppler ultrasound, all access site arteries showed a normal perfusion. Clinically blood pressure control was improved in 11 patients with a significant reduction in systolic and diastolic blood pressure values. Serum creatinine values dropped from 1.81 +/- 0.3 mg/dl to 1.49 +/- 0.3 mg/dl (P < 0.001). Transradial renal artery angioplasty and stenting is technically feasible and safe. Particularly in patients with unfavorable vessel anatomy, this new cranio-caudal approach is an attractive alternative technique.

Aged↗

PubMed2001

Consistent integration of non-reliable heterogeneous information resources applied to the annotation of transmembrane proteins.

Information agents integrate multiple distributed heterogeneous information sources. The challenging yet unsolved problem that remains, is to ensure the semantic consistency of the integrated data. In this paper we set out to develop a general approach to inconsistency management for information agents. It is implemented as part of the EDITtoTrEMBL system and applied on a large real-world problem in the domain of bioinformatics.

Amino Acid Sequence↗

PubMed2001

The nucleotide diversity of MICA and MICB suggests the effect of overdominant selection.

The major histocompatibility complex (MHC) class I-related molecules A and B (MICA and MICB) are stress-inducible cell surface antigens that are recognized by immunocytes bearing the receptor NKG2D. In our study we estimated the average number of synonymous (pis) and nonsynonymous nucleotide substitutions (pia) per site in exons 2-4 of MICA and MICB. In exons 2 and 3 of MICB only nonsynonymous substitutions were found, and in exon 3 of MICA pia clearly exceeded pis. This finding is in contrast to the evolutionary parameters found in most other genes, and is reminiscent of the elevated pia values caused by overdominant selection in the peptide-binding region of conventional MHC class I molecules. It may be explained by the hypothetical interaction with nonpeptide antigens, or by resistance against pathogens.

Evolution, Molecular↗

PubMed2001

A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

Amino Acid Sequence↗

PubMed2001

Homology-based annotation yields 1,042 new candidate genes in the Drosophila melanogaster genome.

The approach to annotating a genome critically affects the number and accuracy of genes identified in the genome sequence. Genome annotation based on stringent gene identification is prone to underestimate the complement of genes encoded in a genome. In contrast, over-prediction of putative genes followed by exhaustive computational sequence, motif and structural homology search will find rarely expressed, possibly unique, new genes at the risk of including non-functional genes. We developed a two-stage approach that combines the merits of stringent genome annotation with the benefits of over-prediction. First we identify plausible genes regardless of matches with EST, cDNA or protein sequences from the organism (stage 1). In the second stage, proteins predicted from the plausible genes are compared at the protein level with EST, cDNA and protein sequences, and protein structures from other organisms (stage 2). Remote but biologically meaningful protein sequence or structure homologies provide supporting evidence for genuine genes. The method, applied to the Drosophila melanogaster genome, validated 1,042 novel candidate genes after filtering 19,410 plausible genes, of which 12,124 matched the original 13,601 annotated genes. This annotation strategy is applicable to genomes of all organisms, including human.

Animals↗

PubMed2001

The relationship of a mother's working model of feeding to her feeding behaviour.

AIMS OF THE STUDY: This study aimed to examine the difference the attunement of a mother's working model of feeding to her infant makes for her positive feeding affect and behaviour, accounting for infant and mother conditions. BACKGROUND/RATIONALE: The concept of a mother's working model of feeding is derived from attachment theory. Caregiving, including feeding, is a component of this theory. The conditions that may influence the attunement of a mother's working model of feeding to her infant include infant birth maturity status (premature, full-term), age at assessment, and robustness, indexed by weight-for-age z score (WAZ). Mother conditions include symptoms of depression and feeding practice (breast feeding or exclusive bottle feeding). DESIGN/METHODS: Participants in this longitudinal study were 99 mothers and their infants (47 full-term, 52 premature, very low birth weight). After written informed consent was given, home assessments were made when infants were approximately 1, 4, 8 and 12 months old (adjusted age for premature infants). Working model attunement was assessed with a video-assisted interview. A mother's positive affect and behaviour, including sensitivity and responsiveness, were rated from videotaped feeding interaction. RESULTS/FINDINGS: Repeated measures analysis with a general linear mixed model showed a significant positive relationship with positive affect and behaviour for both working model attunement and the WAZ score and a significant negative relationship for symptoms of depression. Neither birth maturity status, infant age, nor feeding practice had a significant effect on mother's positive affect and behaviour during feeding. CONCLUSIONS: Nurses' efforts to enhance the attunement of a mother's working model of feeding may help mothers feed with greater positive affect and behaviour. Further study of how the attunement of a mother's feeding expectations and intentions are related to her symptoms of depression and with what she makes of the infant's growth and well-being is needed. The theoretical model needs testing with infants from the entire premature population.

Adult↗

PubMed2001

Extensive cerebral invasion of a basal cell carcinoma of the scalp.

Basal cell carcinomas (BCC) are the most common cutaneous malignant neoplasms affecting fair-skinned human beings. They may progressively enlarge and spread by peripheral extension. Intracranial invasion is very rare. A case of a giant BCC of the scalp invading directly into the left hemisphere through the frontal and parietal lobe and meninges is presented. Brain invasion along Virchow-Robin's spaces is demonstrated histopathologically. A review of literature failed to disclose a previous report of similar extensive and fatal cerebral invasion from a basal cell carcinoma of the scalp.

Brain Neoplasms↗

PubMed2001

Mechanisms of the effects of nicorandil in the isolated rat heart during ischemia and reperfusion: a 31P-nuclear magnetic resonance study.

Nicorandil (SG75) is a potent K+-channel activator with an additional nitro moiety. In the present study we investigated the potential mechanisms (K+-channel activation and nitric oxide [NO] release) for the effects of nicorandil on isolated perfused rat hearts during total global ischemia using 31P-nuclear magnetic resonance. After a 10-min control perfusion, hearts were subjected to treatment with nicorandil-containing (100, 300, or 1000 microM) buffer for 10 min, 15 min of total global ischemia, and 30 min of reperfusion. At high dose (10(-3) M), nicorandil reduced ATP depletion during ischemia by 26% compared with untreated hearts. Blockade of K+ channels by glibenclamide prevented this protective effect. At all doses (10(-4) to 10(-3) M), nicorandil reduced the accumulation of protons during ischemia compared with untreated hearts (pH 6.22 +/- 0.03 vs. 6.02 +/- 0.05 in untreated hearts at the end of ischemia). This effect was preserved after blockade of K+ channels by glibenclamide. Hearts treated with nitroglycerine before ischemia also showed reduced proton accumulation. Therefore, NO release accompanied by increased coronary flow before ischemia, which is caused by the nitro moiety of nicorandil and nitroglycerine treatment, results in reduced proton accumulation. During reperfusion, a pro-arrhythmic effect was observed in hearts treated with the nonpharmacologically high dose of nicorandil (1000 microM). Thus, we conclude that the effects of nicorandil are caused by the simultaneous action of both mechanisms K+-channel activation and NO release. The activation of K+ channels prevents deterioration of ATP during ischemia, whereas NO release and increased coronary flow reduce the accumulation of protons--and thus the decrease in pH--during ischemia.

Animals↗

PubMed2000

Integrating functional genomic information into the Saccharomyces genome database.

The Saccharomyces Genome Database (SGD) stores and organizes information about the nearly 6200 genes in the yeast genome. The information is organized around the 'locus page' and directs users to the detailed information they seek. SGD is endeavoring to integrate the existing information about yeast genes with the large volume of data generated by functional analyses that are beginning to appear in the literature and on web sites. New features will include searches of systematic analyses and Gene Summary Paragraphs that succinctly review the literature for each gene. In addition to current information, such as gene product and phenotype descriptions, the new locus page will also describe a gene product's cellular process, function and localization using a controlled vocabulary developed in collaboration with two other model organism databases. We describe these developments in SGD through the newly reorganized locus page. The SGD is accessible via the WWW at http://genome-www.stanford.edu/Saccharomyces/

Database Management Systems↗

PubMed2000

Interactive visualization and exploration of relationships between biological objects.

Genome sequencing and microarray technology produce ever-increasing amounts of complex data that need analysis. Visualization is an effective analytical technique that exploits the ability of the human brain to process large amounts of data. Here, we review traditional visualization methods based on clustering and tree representation, and also describe an alternative approach that involves projecting objects onto a Euclidean space in a way that reflects their structural or functional distances. Data are visualized without preclustering and can be dynamically explored by the user using 'virtual-reality'. We illustrate this approach with two case studies from protein topology and gene expression.

Biometry↗

PubMed2000

Activity of DNA polymerase alpha in aging human fibroblasts.

During the past decade intense investigation has focused on cellular aging with the expectation of discovering factors that regulate the replication complex and contribute to the onset and progression of cellular aging. The most striking feature of cellular aging is the failure of sensing diploid cells to enter or complete S phase of the cell cycle. The G1/S phase transition is an initial critical step in the regulation of proliferation in eukaryotic cells, and significant advances have been made toward understanding the basic mechanisms of aging by identifying components of the macromolecular assemblies participating in the G1/S transition. These studies have identified multiple DNA polymerases and their accessory factors, and have provided important strategies for investigating the molecular events that contribute to aging processes. DNA replication, repair and recombination in eukaryotic cells require the action of a variety of DNA polymerases, at least six of which are known, alpha, beta, gamma, delta, epsilon, and zeta. Among them the highly conserved DNA polymerase alpha-primase (pol alpha-primase) is the only enzyme capable of initiating DNA replication at chromosomal origin sites and at sites of initiation of discontinuous synthesis of Okazaki fragments on the lagging side of the replication fork. Numerous protein factors that play strategic roles in DNA replication have been identified and the understanding of their regulation has been an important step for identifying the elements that are involved in, and possibly necessary for, governing cellular senescence and aging. In this review we summarize the current information regarding DNA pol alpha modulation during aging. We focus in particular on the coordinated actions of DNA pol alpha in the presence of other cellular proteins involved in the replication complex in the hope that understanding pol alpha interactions with components of the replication complex may provide insight into the mechanisms by which aging and age-related diseases occur.

Aging↗