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Biomedical subjects

R Simon

Publications and source records attributed to R Simon.

At least 127 records · Page 7Linked to original sources
PubMed1998

Data management and analysis for gene expression arrays.

Microarray technology makes it possible to simultaneously study the expression of thousands of genes during a single experiment. We have developed an information system, ArrayDB, to manage and analyse large-scale expression data. The underlying relational database was designed to allow flexibility in the nature and structure of data input and also in the generation of standard or customized reports through a web-browser interface. ArrayDB provides varied options for data retrieval and analysis tools that should facilitate the interpretation of complex hybridization results. A sampling of ArrayDB storage, retrieval and analysis capabilities is available (www.nhgri.nih.gov/DIR/LCG/15K/HTML/ ), along with information on a set of approximately 15,000 genes used to fabricate several widely used microarrays. Information stored in ArrayDB is used to provide integrated gene expression reports by linking array target sequences with NCBI's Entrez retrieval system, UniGene and KEGG pathway views. The integration of external information resources is essential in interpreting intrinsic patterns and relationships in large-scale gene expression data.

Computer Communication Networks↗
PubMed1998

Comparative genomic hybridization and telomerase activity analysis identify two biologically different groups of 4s neuroblastomas.

Chromosomal aberrations of 20 stage 4s neuroblastomas were analysed by comparative genomic hybridization (CGH). In a subset of 13/20 tumours, telomerase activity was evaluated by the telomeric repeat amplification protocol (TRAP). The CGH data were compared with the CGH results of ten stage 1 and 2 (stage 1/2) and 22 stage 3 and 4 (stage 3/4) neuroblastomas. A total of 17/20 stage 4s neuroblastomas did not progress clinically, whereas tumour progression with lethal outcome occurred in 3/20 cases. The CGH data of clinically non-progressing stage 4s tumours revealed a high rate of whole-chromosome aberrations (73.4%) with an overrepresentation of mainly chromosomes 2, 6, 7, 12, 13, 17, 18 and an underrepresentation of mainly chromosomes 3, 4, 11, 14. MYCN amplification or 1p deletion was observed in only 1/27 or 2/17 clinically non-progressing stage 4s tumours respectively, whereas all three progressive stage 4s neuroblastomas showed MYCN amplification, 1p deletion and, in 2/3 cases, distal 17q gains. Except for one case, telomerase activity was not observed in non-progressing stage 4s neuroblastomas. In contrast, 4s tumours with lethal outcome revealed elevated telomerase activity levels. Our data suggest that stage 4s neuroblastomas belong to two biologically different groups, one of which displays the genetic features of localized stage 1/2 tumours, whereas the other mimics advanced stage 3/4 neuroblastomas.

Blotting, Southern↗
PubMed1998

The relationship of packed cell transfusion to red blood cell deformability in systemic inflammatory response syndrome patients.

RBC deformability (RBCD) is decreased in critically ill patients. This is thought to impede the passage of the RBC through the microcirculation. The cell transit analyzer (CTA) provides an evaluation of RBCD. RBCD was examined in 16 patients admitted to the surgical intensive care unit. CTA analysis was conducted within 24 h of admission to the surgical intensive care unit or as soon as possible thereafter, and then repeated every 72 h. Counts per second (C/s) was the parameter used as an index of RBCD. Patients were classified as Septic/SIRS or nonseptic at the time of each blood collection by standard clinical criteria. There were 34 total specimens, 22 septic/SIRS and 12 nonseptic. The C/s for the SIRS samples (41.7 +/- 3.4 was significantly (p < .05) lower than that of the non-SIRS samples (54.3 +/- 5.3). Seventeen of the Septic/SIRS samples were obtained following blood transfusion. Pearson's test calculated for the C/s and the total number of packed RBC transfusions showed a positive correlation (r = .594) that was statistically significant (p < .02). CTA was also performed on 10 U of banked packed RBC in vitro. Deformability was maintained at a constant level until the very end of the storage period, at which time there was a statistically significant decrease in C/s (p < .0001). These data suggest that packed RBC transfusion is associated with a significant improvement in the abnormally low RBCD seen in critically ill patients. This may be due to replacement of previously rigidified cells by cells with a more normal RBCD.

Adult↗
PubMed1998

Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma.

PURPOSE: Primary CNS lymphoma (PCNSL) and primary intraocular lymphoma (IOL) are usually treated with radiation therapy alone or in combination with chemotherapy. The neurotoxicity of these treatments can be substantial. This study attempts to define the toxicity and efficacy of the treatment of this disease with chemotherapy alone. PATIENTS AND METHODS: Fourteen nonimmunocompromised patients were accrued to a chemotherapy regimen that incorporated a 24-hour infusion of high-dose methotrexate total dose of 8.4 g/m2 with leucovorin rescue; thiotepa 35 mg/m2; vincristine 1.4 mg/m2; dexamethasone; and intrathecal cytarabine (Ara-C) and methotrexate (MTV) administered in 21-day cycles. Seven patients were prospectively followed up with formal neuropsychologic assessments for evidence of CNS toxicity. RESULTS: The response rate was 100% with 11 (79%) complete responses and three (21%) partial responses. Cumulative survival and progression-free survival rates at more than 4.5 years were 68.8% and 34.3%, respectively. Median survival has not been reached, and median progression-free survival was 16.5 months. Toxicity included severe leukoencephalopathy that was clearly attributable to chemotherapy (two patients), grade 3 or 4 neutropenia in 50% of the cycles administered, ileus (one patient), and seizures (two patients). Mucositis and renal and hepatic toxicity were mild and not therapy limiting. CONCLUSION: The MTV regimen is generally well tolerated and produces a high complete response rate. Chemotherapy alone should be investigated further in this disease to assess the necessity of initial radiation therapy, either alone or in combined modality regimens, for the achievement of optimal response and survival.

Adult↗
PubMed1998

[Comparative genomic hybridization (CGH) for detecting a heretofore undescribed amplified chromosomal segment in high-grade medullary osteosarcoma].

Osteosarcoma is one of the most commonly biopsied primary tumor of bone. High-grade osteosarcomas in particular exhibit a wide spectrum of cytogenetic changes. Molecular cytogenetic studies on osteosarcomas have shown that genomic amplification, especially of both the TP53-binding MDM2 gene and the flanking SAS gene, plays an important role in the biology of these tumors. We applied CGH in order to obtain a global view of DNA-sequence losses and gains in osteosarcoma. CGH was performed on 20 high-grade medullary osteosarcomas (13 primary tumors prior to chemotherapy, 5 tumors after chemotherapy, 2 established cell lines [MB63, HOS58]) using genomic DNA of snap-frozen tumor specimens. CGH revealed DNA copy number aberrations, mostly gains, in all the tumors studied with an average of 18.5 aberrations/tumor (range 8-32). High-level amplifications were observed in all cases (average 4.1 amplifications/tumor [range 1-10]). Amplicons affecting at least five tumors were mapped to 1p21-31 (9/20 cases), 3q25-qter (6/20), 6p12-21 (6/20), 8q12-qter (10/20), 12p11-12 (9/20), 12q12-15 (enclosing MDM2 and SAS loci, 7/20). Losses were most frequently seen at 3p, 10q, 11p and 13 (all 10/20). In conclusion, our CGH data indicated that genomic amplification plays an important role in the biology of osteosarcoma. CGH demonstrated the complexity of genetic aberrations in osteosarcomas. The detection of novel non-random DNA amplifications in our study has defined regions for further targeted molecular genetic research aimed at identifying those oncogenes that are characteristic of osteosarcoma development.

Bone Neoplasms↗
PubMed1998

[Evidence of genetic alterations in chromosome 11 in embryonal and alveolar rhabdomyosarcoma].

Various chromosome 11 alterations have been described in rhabdomyosarcoma (RMS). Allelic losses of 11p15.5 are characteristic of embryonal RMS (eRMS), whereas an increase in the expression of the Igf2 gene located on 11p15.5 has regularly been observed in eRMS and alveolar RMS (aRMS). The aim of our study was to analyse chromosome 11 alterations of RMS by combining different molecular-genetic and cytogenetic methods. 16 RMSs (7 aRMS with proven 2;13 or 1;13 translocations, 9 eRMS) were studied by a PCR-based microsatellite analysis of loci 11p15.5 and 11q23. Comparative genomic hybridization (CGH) was performed in 8/16 cases. The ploidy status of chromosome 11 was evaluated using the FISH technique. A RT-PCR analysis of Igf2 gene region was performed to evaluate the imprinting status. Allelic losses (LOH) of 11p15.5 were observed in 4/7 aRMS and 8/9 eRMS. These losses were accompanied by LOH of 11q23 in 2/7 aRMS and 5/9 eRMS, respectively. CGH of all the eRMSs and one aRMS studied revealed gains of genetic material mostly involving the entire length of chromosome 11. One aRMS showed a loss of chromosome 11 material, both in CGH and LOH analysis. In 2/9 aRMS, which neither in CGH nor in LOH analysis had exhibited chromosome 11 alterations, biallelic IGF-II expression was revealed. Our results show that chromosome 11 alterations play a major role in the biology of both alveolar and eRMS. Combining the data of our study, we demonstrated that three different chromosome 11 alterations are involved in the tumorigenesis of RMS: 1) LOH resulting in hemizygosity of chromosome 11. 2) LOH with simultaneous gains of chromosome 11 material due to uniparental polysomy. 3) loss of imprinting for the Igf2 gene in the absence of gross chromosome 11 alterations.

Chromosome Aberrations↗
PubMed1998

The regulation of flowering time by daylength in Arabidopsis.

We are studying several Arabidopsis mutants that show altered regulation of flowering time in response to daylength. One of the mutations we are studying, constans, delays flowering under long days but has no effect under short days. Analysis of the expression of the CONSTANS gene, and modification of its expression in transgenic plants, suggests that this gene promotes flowering in response to long days and that the delay in flowering that occurs in wild-type plants under short days is at least in part due to regulation of CONSTANS gene transcription. We describe genetic approaches that we are taking to identify genes that act in the same genetic pathway as CONSTANS, and in particular the relationship between CONSTANS and two other genes that we are studying. These are LATE ELONGATED HYPOCOTYL, for which we have a dominant mutant allele that causes late flowering, and EARLY SHORT DAYS 4, whose inactivation causes early flowering. In addition to their effects on flowering time, the over-expression of CONSTANS and the inactivation of EARLY SHORT DAYS 4 cause the Arabidopsis shoot to become determinate and therefore to terminate development prematurely. This phenotype is discussed in light of other genes that have previously been shown to be required to maintain indeterminate development of the shoot.

Arabidopsis↗
PubMed1998

Heterogeneity of noninvasive arrhythmic risk indicators in patients with ischemic cardiomyopathy.

Noninvasive electrocardiographic variables for arrhythmic risk stratification in chronic heart failure are of great clinical interest but remain highly controversial. This study analyzed repolarization dispersion, heart rate variability, ventricular ectopic activity, and hemodynamic parameters in 30 patients with ischemic heart failure and in 20 normal control subjects. The values for all parameters were distinctly separated between the failure and control group. Left ventricular ejection fraction had a strong relation to ventricular ectopic activity (r = .54), a weak association with repolarization dispersion (r = .29), and seemingly no parallels with heart rate variability (r = .12). However, no linear association could be detected between any of the arrhythmic risk indicators (r = .10-.22), whereas a number of linearly related angiographic-hemodynamic variables readily defined the mechanical risk profile. Thus, alterations of noninvasive arrhythmic risk indicators in heart failure are not uniform, which confounds approaches for a composite ECG risk score in individual patients.

Arrhythmias, Cardiac↗
PubMed1998

Bayesian variable selection method for censored survival data.

A Bayesian variable selection method for censored data is proposed in this paper. Based on the sufficiency and asymptotic normality of the maximum partial likelihood estimator, we approximate the posterior distribution of the parameters in a proportional hazards model. We consider a parsimonious model as the full model with some covariates unobserved and replaced by their conditional expected values. A loss function based on the posterior expected estimation error of the log-risk for the proportional hazards model is used to select a parsimonious model. We derive computational expressions for this loss function for both continuous and binary covariates. This approach provides an extension of Lindley's (1968, Journal of the Royal Statistical Society, Series B 30, 31-66) variable selection criterion for the linear case. Data from a randomized clinical trial of patients with primary biliary cirrhosis of the liver (PBC) (Fleming and Harrington, 1991, Counting Processes and Survival Analysis) is used to illustrate the proposed method and a simulation study compares it with the backward elimination procedure.

Bayes Theorem↗
PubMed1997

Recanalization of total coronary occlusions using a laser guidewire (the European TOTAL Surveillance Study).

The success rates of coronary angioplasty for the treatment of chronic total occlusions are less favorable than for coronary stenosis. Therefore, a new laser guidewire (LW) was designed to facilitate the crossing of chronic total occlusions. We report on the results of a European multicenter surveillance study, evaluating the laser guidewire performance. Between May 1994 and July 1996, 345 patients (age 59 +/- 10 years, 291 men) with chronic total occlusions were enrolled in 28 European centers. The median age of occlusion was 29 weeks (range 2 to 884), the occlusion length 19 +/- 10 mm. LW recanalization was successful in 205 patients (59%/). LW perforation occurred in 73 patients (21%), with hemodynamic consequences in 4 (1%). There were no deaths, emergency coronary artery bypass graft surgery, or Q-wave myocardial infarctions. In a multivariate regression analysis an occlusion age of <40 weeks (p = 0.001, RR = 1.34) and an occlusion length <30 mm (p = 0.01, RR = 1.59) were independent predictors of success. Results indicate that the LW is an effective and safe tool in the treatment of chronic total occlusion refractory to conventional guidewires.

Chronic Disease↗
PubMed1997

Large sample Bayesian inference on the parameters of the proportional hazard models.

This paper considers large sample Bayesian analysis of the proportional hazards model when interest is in inference on the parameters and estimation of the log relative risk for specified covariate vectors rather than on prediction of the survival function. We use a normal prior distribution for the parameters and make inferences based on the derived posterior distribution. The suggested approach is much simpler than alternative Bayesian analyses previously suggested for the proportional hazards models. Using simulated data we compare estimates obtained from the Bayesian analysis with those obtained from the full proportional hazards model and the reduced model after backwards elimination. We show that under a wider range of assumptions, the Bayesian analysis provides reduced estimation errors and improved rejection of noise variables. Finally, we illustrate the methodology using data from a large study of prognostic markers in breast cancer.

Bayes Theorem↗
PubMed1997

Dual role for fimbriata in regulating floral homeotic genes and cell division in Antirrhinum.

The fimbriata (fim) gene of Antirrhinum affects both the identity and arrangement of organs within the flower, and encodes a protein with an F-box motif. We show that FIM associates with a family of proteins, termed FAPs (FIM-associated proteins), that are closely related to human and yeast Skp1 proteins. These proteins form complexes with F-box-containing partners to promote protein degradation and cell cycle progression. The fap genes are expressed in inflorescence and floral meristems in a pattern that incorporates the domain of fim expression, supporting an in vivo role for a FIM-FAP complex. Analysis of a series of novel fim alleles shows that fim plays a key role in the activation of organ identity genes. In addition, fim acts in the regions between floral organs to specify the correct positioning and maintenance of morphological boundaries. Taking these results together, we propose that FIM-FAP complexes affect both gene expression and cell division, perhaps by promoting selective degradation of regulatory proteins. This may provide a mechanism by which morphological boundaries can be aligned with domains of gene expression during floral development.

Amino Acid Sequence↗
PubMed1997

Accelerated titration designs for phase I clinical trials in oncology.

BACKGROUND: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. PURPOSE: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. METHODS: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0-1 in the previous course for that patient. RESULTS: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively. CONCLUSION: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are under-treated, speed the completion of phase I trials, and provide a substantial increase in the information obtained.

Antineoplastic Agents↗
PubMed1997

Coagulation activation in patients undergoing directional coronary atherectomy.

Restenosis is a major problem of percutaneous transluminal coronary angioplasty (PTCA) and related procedures. To better understand the underlying pathophysiologic mechanisms, coagulation and fibrinolytic variables were analysed prospectively in 35 patients after directional coronary atherectomy (DCA) and in 20 control patients undergoing diagnostic heart catheterisation and coronary angiography. Blood samples were taken before and 1 h, 24 h and 48 h after the procedure. No subacute thrombosis or unstable angina were documented in any patient. In 8 out of these 35 patients late restenosis was diagnosed during follow-up angiography 3-6 months after DCA. In these 8 patients prothrombin fragments (F1 + 2) rose from 0.7 to 0.9 nmol/l (P < 0.01) and thrombin-antithrombin III complexes (TAT) from 2.9 to 6.0 micrograms/l (P < 0.01), but not significantly in 27 patients without restenosis and in the control patients. In patients with late restenosis plasminogen activator inhibitor (PAI-1) also increased from 2.4 to 4.9 U/ml (P < 0.05) 24 h after DCA while there were no significant changes in patients without restenosis and in control patients. D-Dimer/TAT ratio reflecting the balance between clotting activation and fibrinolysis was significantly lower after 24 h in restenosis patients. The findings suggest that coagulation activation and hypofibrinolysis during 48 h after DCA might be associated with the development of late restenosis.

Adult↗
PubMed1997

Comparative genomic hybridization (CGH) analysis of neuroblastomas--an important methodological approach in paediatric tumour pathology.

Comparative genomic hybridization (CGH) was applied to 35 neuroblastomas to obtain a global view of genetic imbalances. Results were validated by means of Southern blot hybridization (detection of N-myc amplification), loss of heterozygosity (LOH) studies (detection of deletion 1p), and interphase cytogenetics [dual labelling fluorescence in situ hybridization (FISH) of centromeric 17 and erbB-2]. CGH allowed sensitive detection of N-myc amplification and chromosome 1p deletion, representing the most established prognostic markers of neuroblastoma. In addition, a high rate of chromosome 17 aberrations (63 per cent) with possible prognostic relevance was observed. Previously unreported high level copy number increases indicating oncogene amplification were mapped to chromosome subbands 2p13-14 and 3q24-26. Other recurrent regional chromosomal aberrations were localized on 11q, 12q, 13q, 14q, and 15q. CGH results were fully consistent with data of Southern blot analysis and LOH study, as well as interphase cytogenetics. These results show that CGH is a sensitive method for the detection of all prognostically relevant genetic alterations in neuroblastomas; that CGH considerably simplifies the detection of these alterations, resulting in a single methodological approach; and that CGH is a powerful tool to elucidate previously unknown genetic changes in neuroblastomas.

Blotting, Southern↗
PubMed1997

[Endomyocardial biopsy--helpful in differential diagnosis between myocarditis and dilated cardiomyopathy. A case report].

Endomyocardial biopsy is an established technique to distinguish between myocarditis and dilated cardiomyopathy. Even when clinical symptoms for myocarditis are lacking, immunohistologic findings may establish a clear diagnosis. For treatment, however, an early diagnosis is mandatory. We report on a 44 year old patient who was admitted with the echocardiographic diagnosis of dilated cardiomyopathy. He underwent diagnostic angiocardiography and endomyocardial biopsy. The latter demonstrated an active myocarditis. At the time of read-mission, 2 weeks later, the patient had deteriorated. Now, additional to a symptomatic therapy, prednisolone, azathioprine and human immunoglobulin G were given and patient conditions improved dramatically. The use of endomyocardial biopsy seems recommendable in order to define patients diagnosis and their results may be necessary to decide patients therapy.

Adult↗