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PubMed1988

Limits of normal left ventricular dimensions in growth and development: analysis of dimensions and variance in the two-dimensional echocardiograms of 268 normal healthy subjects.

The majority of studies generating normal echocardiographic reference values for left ventricular dimensions have been based on blindly performed M-mode measurements, and there are no previous reports based on two-dimensional echocardiography that provide a comprehensive analysis of the two-dimensional measurements from infancy to old age. This report presents the results of analyzing the left ventricular internal dimensions from cross-sectional echocardiographic studies on 268 normal healthy subjects (none were hospitalized for any reason) whose ages ranged from 6 days to 76 years. The mean data are reported as functions of body surface area and, in addition, the variance is modeled as a function of body surface area to provide an accurate and clinically useful determination of normal limits and to model changes in the cardiac dimensions and in their variance representing normal growth and development. The data fit well to the exponential growth model (r values 0.85 to 0.95). Variance about the central values also depended significantly on body size; that relation is represented effectively by a quadratic function of body surface area (r values 0.82 to 0.98). The model parameters allow calculation of normal limits at any desired level of confidence. Areas determined by hand planimetry have significantly greater variance compared with variance of linear dimensions, and also compared with variance of cross-sectional area using ellipses generated from the anteroposterior and mediolateral dimensions. This implies that either biologic variations in the amount of infolding or errors in freehand planimetry constitute a significant source of variance; this may be remedied by filtering out high frequency oscillations of contour. There is no significant difference in midnormal values and confidence limits for corresponding dimensions measured from orthogonal views. Furthermore, the anteroposterior and mediolateral dimensions of the left ventricle superimpose at each body size, consistent with circular cross section for normal subjects throughout growth and development. The data presented should comprise a useful set of reference standards for interpretation of cross-sectional echocardiograms.

Adolescent↗
PubMed2025

Benchmark for Quantitative Global and Redox Proteomics Analysis by Combining Protein-Aggregation Capture and Data Independent Acquisition.

Oxidative damage plays a critical role in various diseases including cardiovascular and neurological disorders. Thiol redox reactions, acting as oxidative stress sensors, influence protein structure and function. Redox proteomics, based on the differential alkylation of cysteine sites followed by mass spectrometry, enables the comprehensive analysis of thiol redox status in cells and tissues. However, these approaches require extensive sample manipulation and are not compatible with data-independent acquisition techniques. Here, we introduce PACREDOX, an innovative strategy based on protein aggregation capture (PAC), and demonstrate its compatibility with library-free DIA. Compared with traditional methods such as FASILOX, PACREDOX reduces preparation time and costs while maintaining thiol and proteome coverage. To enable library-free DIA, we corrected in silico spectral libraries in DIA-NN using experimental retention time data from methylthiolated-Cys peptides. PACREDOX with DIA was benchmarked against FASILOX in a myocardial infarction model, yielding the same biological insights, while enhancing peptide and protein coverage. Our results underscore the potential and efficiency of this methodology for studying oxidative damage. Overall, PACREDOX offers an automatable, high-throughput, and cost-effective strategy for redox proteomics.

Proteomics↗
PubMed1992

[An epidemiological analysis on the geographic factors of esophageal cancer].

The author collects the data of esophageal cancer mortality (1971-1973) of 78 counties in Hubei Province and the data of topography, climate, soil, rock formation and geochemical elements, including 40 suspected factors. The method of linear correlation and multiple stepwise regression are used for the comprehensive analysis of relation between the geographical factors and esophageal cancer. The result is that four factors metamorphic rock, zinc, copper, chromium are suspected factors. It suggests that the four factors will need future study.

China↗
PubMed2007

Ab and T cell epitopes of influenza A virus, knowledge and opportunities.

The Immune Epitope Database and Analysis Resources (IEDB) (www.immuneepitope.org) was recently developed to capture epitope related data. IEDB also hosts various bioinformatics tools that can be used to identify novel epitopes as well as to analyze and visualize existing epitope data. Herein, a comprehensive analysis was undertaken (i) to compile and inventory existing knowledge regarding influenza A epitopes and (ii) to determine possible cross-reactivities of identified epitopes among avian H5N1 and human influenza strains. At present, IEDB contains >600 different epitopes derived from 58 different strains and 10 influenza A proteins. By using the IEDB analysis resources, conservancy analyses were performed, and several conserved and possibly cross-reactive epitopes were identified. Significant gaps in the current knowledge were also revealed, including paucity of Ab epitopes in comparison with T cell epitopes, limited number of epitopes reported for avian influenza strains/subtypes, and limited number of epitopes reported from proteins other than hemagglutinin and nucleoprotein. This analysis provides a resource for researchers to access existing influenza epitope data. At the same time, the analysis illustrates gaps in our collective knowledge that should inspire directions for further study of immunity against the influenza A virus.

Animals↗
PubMed2002

Biological factors are more important than socio-demographic and psychosocial conditions in relation to hypertension in middle-aged women. The Women's Health in the Lund Area (WHILA) study.

The objective of this cross-sectional study was to analyse the influence of biological, socio-demographic, and psychosocial factors and current perimenopausal status on hypertension in a geographically defined population of 10,766 women aged 50-59 years, of whom 6901 attended the study. Altogether 1887 (27.3%) women had hypertension: 996 with drug treatment and 891 diagnosed at the study. In a logistic multiple regression analysis (controlled for age), drug treatment of hyperlipidaemia, family history of hypertension, waist-to-hip ratio, body mass index (BMI) increase > or = 25% during the past 25 years, S-triglycerides, S-cholesterol, education up to comprehensive school, and to upper secondary school, consumption of 84-167 g of alcohol/week, and of > or = 168 g of alcohol/week, were positively associated with hypertension, while high-density lipoprotein cholesterol and current smoking were negatively associated. A significant interaction was found between current smoking and BMI increase, with a lower risk for hypertension among smokers who had increased their BMI > or = 25%. No interaction was found between smoking and alcohol. In conclusion, hypertension was predominantly associated with biological factors, and with heredity for hypertension. Of the socio-demographic factors, only low level of education was associated with hypertension in a comprehensive analysis. Perimenopausal status showed no relation to occurrence of hypertension in the multiple regression analysis. The risk for hypertension increased with moderate and high consumption of alcohol, whereas smoking showed a decreased risk. Among women with weight gain, present smoking remained protective. Although both smoking and hypertension are established risk factors for cardiovascular disease, they seem not to be directly linked, indicating a complexity of mechanisms.

Alcohol Drinking↗
PubMed1991

Genetic exchange across a paracentric inversion of the mouse t complex.

Mouse t haplotypes are distinguished from wild-type forms of chromosome 17 by four nonoverlapping paracentric inversions which span a genetic distance of 20 cM. These inversion polymorphisms are responsible for a 100-200-fold suppression of recombination which maintains the integrity of complete t haplotypes and has led to their divergence from the wild-type chromosomes of four species of house mice within which t haplotypes reside. As evidence for the long period of recombinational isolation, alleles that distinguish all t haplotypes from all wild-type chromosomes have been established at a number of loci spread across the 20-cM variant region. However, a more complex picture emerges upon analysis of other t-associated loci. In particular, "mosaic haplotypes" have been identified that carry a mixture of wild-type and t-specific alleles. To investigate the genetic basis for mosaic chromosomes, we conducted a comprehensive analysis of eight t complex loci within 76 animals representing 10 taxa in the genus Mus, and including 23 previously characterized t haplotypes. Higher resolution restriction mapping and sequence analysis was also performed for alleles at the Hba-ps4 locus. The results indicate that a short tract of DNA was transferred relatively recently across an inversion from a t haplotype allele of Hba-ps4 to the corresponding locus on a wild-type homolog leading to the creation of a new hybrid allele. Several classes of wild-type Hba-ps4 alleles, including the most common form in inbred strains, appear to be derived from this hybrid allele. The accumulated data suggest that a common form of genetic exchange across one of the four t-associated inversions is gene conversion at isolated loci that do not play a role in the transmission ratio distortion phenotype required for t haplotype propagation. The implications of the results pose questions concerning the evolutionary stability of gene complexes within large paracentric inversions and suggest that recombinational isolation may be best established for loci residing within a short distance from inversion breakpoints.

Animals↗
PubMed2001

Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.

With the complete human genomic sequence being unraveled, the focus will shift to gene identification and to the functional analysis of gene products. The generation of a set of cDNAs, both sequences and physical clones, which contains the complete and noninterrupted protein coding regions of all human genes will provide the indispensable tools for the systematic and comprehensive analysis of protein function to eventually understand the molecular basis of man. Here we report the sequencing and analysis of 500 novel human cDNAs containing the complete protein coding frame. Assignment to functional categories was possible for 52% (259) of the encoded proteins, the remaining fraction having no similarities with known proteins. By aligning the cDNA sequences with the sequences of the finished chromosomes 21 and 22 we identified a number of genes that either had been completely missed in the analysis of the genomic sequences or had been wrongly predicted. Three of these genes appear to be present in several copies. We conclude that full-length cDNA sequencing continues to be crucial also for the accurate identification of genes. The set of 500 novel cDNAs, and another 1000 full-coding cDNAs of known transcripts we have identified, adds up to cDNA representations covering 2%--5 % of all human genes. We thus substantially contribute to the generation of a gene catalog, consisting of both full-coding cDNA sequences and clones, which should be made freely available and will become an invaluable tool for detailed functional studies.

3' Untranslated Regions↗
PubMed1999

Deconvolution analysis for absorption and metabolism of aspirin in microcapsules.

We have previously proposed a novel deconvolution method, which can estimate first-pass metabolism of orally administered drugs. In the present study, we examined whether this deconvolution method is useful for evaluating oral dosage forms. The absorption and first-pass metabolism of orally administered aspirin formulated in several forms were analyzed. Two types of microcapsules consisting of Eudragit L100 alone and Eudragit L100/ethylcellulose (4:6) were prepared as sustained release formulations, for comparison with aspirin in powder form. The deconvolution analysis revealed that absorption of aspirin was sustained by encapsulating it in microcapsules. Interestingly, it also revealed that the percentage metabolized during absorption was different among the three types of formulations. Thus, the deconvolution method has enabled a comprehensive analysis of orally administered drugs. This method is believed to contribute to the evaluation of oral drug formulations.

Absorption↗
PubMed2003

Information warehouse as a tool to analyze Computerized Physician Order Entry order set utilization: opportunities for improvement.

A Computerized Physician order entry (CPOE) system was successfully implemented at the Ohio State University Medical Center (OSUMC) in February 2000. The electronic entry and use of order sets is designed to standardize patient care and improve efficiency and patient safety. To evaluate the effectiveness of the CPOE system and to maximize its benefits, one needs to easily access and analyze the data. Since the CPOE system is not equipped to support such on demand analysis, the data from the system is extracted daily into the OSUMC's Information Warehouse (IW). This allows the CPOE data to be linked with other clinical and financial patient information in the IW to provide detailed and comprehensive analysis. Our focus in this paper is the use of the IW as a tool to analyze order set usage patterns and the opportunities such analysis provides for improvements in education, resource utilization and patient care.

Academic Medical Centers↗
PubMed2003

Quantitative analysis of the fluorescence properties of intrinsically fluorescent proteins in living cells.

The main potential of intrinsically fluorescent proteins (IFPs), as noninvasive and site-specific markers, lies in biological applications such as intracellular visualization and molecular genetics. However, photophysical studies of IFPs have been carried out mainly in aqueous solution. Here, we provide a comprehensive analysis of the intracellular environmental effects on the steady-state spectroscopy and excited-state dynamics of green (EGFP) and red (DsRed) fluorescent proteins, using both one- and two-photon excitation. EGFP and DsRed are expressed either in the cytoplasm of rat basophilic leukemia (RBL-2H3) mucosal mast cells or anchored (via LynB protein) to the inner leaflet of the plasma membrane. The fluorescence lifetimes (within approximately 10%) and spectra in live cells are basically the same as in aqueous solution, which indicate the absence of both IFP aggregation and cellular environmental effects on the protein folding under our experimental conditions. However, comparative time-resolved anisotropy measurements of EGFP reveal a cytoplasmic viscosity 2.5 +/- 0.3 times larger than that of aqueous solution at room temperature, and also provide some insights into the LynB-EGFP structure and the heterogeneity of the cytoplasmic viscosity. Further, the oligomer configuration and internal depolarization of DsRed, previously observed in solution, persists upon expression in these cells. DsRed also undergoes an instantaneous three-photon induced color change under 740-nm excitation, with efficiently nonradiative green species. These results confirm the implicit assumption that in vitro fluorescence properties of IFPs are essentially valid for in vivo applications, presumably due to the beta-barrel protection of the embodied chromophore. We also discuss the relevance of LynB-EGFP anisotropy for specialized domains studies in plasma membranes.

Animals↗
PubMed2026

Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.

PURPOSE: Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a prespecified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS data was also assessed. RESULTS: This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes. See related commentary by Gupta et al., p. 3718.

Humans↗
PubMed2007

Credentialing preclinical pediatric xenograft models using gene expression and tissue microarray analysis.

Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets.

Cell Line, Tumor↗
PubMed2006

Saccharomyces cerevisiae a-factor mutants reveal residues critical for processing, activity, and export.

The Saccharomyces cerevisiae mating pheromone a-factor provides a paradigm for understanding the biogenesis of prenylated fungal pheromones. The biogenesis of a-factor involves multiple steps: (i) C-terminal CAAX modification (where C is cysteine, A is aliphatic, and X is any residue) which includes prenylation, proteolysis, and carboxymethylation (by Ram1p/Ram2p, Ste24p or Rce1p, and Ste14p, respectively); (ii) N-terminal processing, involving two sequential proteolytic cleavages (by Ste24p and Axl1p); and (iii) nonclassical export (by Ste6p). Once exported, mature a-factor interacts with the Ste3p receptor on MATalpha cells to stimulate mating. The a-factor biogenesis machinery is well defined, as is the CAAX motif that directs C-terminal modification; however, very little is known about the sequence determinants within a-factor required for N-terminal processing, activity, and export. Here we generated a large collection of a-factor mutants and identified residues critical for the N-terminal processing steps mediated by Ste24p and Axl1p. We also identified mutants that fail to support mating but do not affect biogenesis or export, suggesting a defective interaction with the Ste3p receptor. Mutants significantly impaired in export were also found, providing evidence that the Ste6p transporter recognizes sequence determinants as well as CAAX modifications. We also performed a phenotypic analysis of the entire set of isogenic a-factor biogenesis machinery mutants, which revealed information about the dependency of biogenesis steps upon one another, and demonstrated that export by Ste6p requires the completion of all processing events. Overall, this comprehensive analysis will provide a useful framework for the study of other fungal pheromones, as well as prenylated metazoan proteins involved in development and aging.

ATP-Binding Cassette Transporters↗
PubMed2004

HELEN, a modular framework for representing and implementing clinical practice guidelines.

OBJECTIVES: In order to implement clinical practice guidelines for the Department of Neonatology of the Heidelberg University Medical Center we developed a modular framework consisting of tools for authoring, browsing and executing encoded clinical practice guidelines (CPGs). METHODS: Based upon a comprehensive analysis of literature, we set up requirements for guideline representation systems. Additionally, we analyzed further aspects such as the critical appraisal and known bridges and barriers for implementing CPGs. Thereafter we went through an evolutionary spiral model to develop a comprehensive ontology. Within this model each cycle focuses on a certain topic of management and implementation of CPGs. RESULTS: In order to bring the resulting ontology into practice we developed a framework consisting of a tool for authoring, a server for web-based browsing, and an engine for the execution of certain elements of CPGs. Based upon this framework we encoded and implemented several CPGs in varying medical domains. CONCLUSIONS: This paper shall present a practical framework for both authors and implementers of CPGs. We have shown the fruitful combination of different knowledge representations such as narrative text and algorithm for implementing CPGs. Finally, we introduced a possible approach for the explicit adaptation of CPGs in order to provide institution-specific recommendations and to support sharing with other medical institutions.

Academic Medical Centers↗
PubMed2026

Metabolic Dysfunction-Associated Steatotic Liver Disease Is Associated With Adverse Social Factors: An Analysis Using All of Us.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is progressive, with estimated global prevalence exceeding 30%. Social determinants of health (SDOH) may impact MASLD risk and progression. However, this has not been fully characterized. We harnessed the power of the All of Us Research Program (AoU) dataset to conduct a comprehensive analysis examining the association between various SDOH and MASLD. METHODS: We conducted a retrospective cross-sectional analysis of the AoU database. We identified participants with MASLD using ICD-9 and -10 codes and excluded individuals with other chronic liver diseases or self-reported heavy alcohol use. Healthy control participants were devoid of chronic liver diseases, heavy alcohol use, and comorbidities associated with MASLD if obese. We examined SDOH by combining relevant questions from various AoU surveys and conducted univariate and multivariate logistic regression to examine the association between various SDOH and MASLD. RESULTS: After matching cases to controls by age and race/ethnicity, the sample of 57,895 participants had a 1:3 case to control ratio; 16,666 had complete SDOH survey data (MASLD to controls, 1:3.4). Compared to controls, individuals with MASLD were more likely to have less than a high school education (10.7% vs 9.7%; P < .001) and annual income &#x2264;$35,000 (42.4% vs 34.3%; P < .001). Compared to controls, participants with MASLD had significantly higher levels of social isolation, neighborhood disorder, perceived stress, food insecurity, and transportation insecurity (P < .001 for all). CONCLUSION: The study identified significant associations between MASLD and multiple SDOH. Future studies should investigate how SDOH interact to drive MASLD risk and progression.

All of Us↗
PubMed2007

Cost-utility analysis of treatment algorithms for moderate grade vesicoureteral reflux using Markov models.

PURPOSE: The optimal treatment algorithm for vesicoureteral reflux remains controversial. Previous decision analyses have attempted to determine the best approach solely from the cost or cure perspective but have not combined the goals of minimizing treatment and disease burden. We incorporated these considerations into a contemporary, comprehensive analysis of treatment for vesicoureteral reflux. MATERIALS AND METHODS: We examined costs from the perspective of the medical institution, and utility from the perspective of parents of children with grades II and III vesicoureteral reflux. Cost-utility analysis using Markov modeling was performed to ascertain which of 5 treatment algorithms best minimized morbidity and cost. A higher utility value was based on minimizing treatment and disease burden. Measures of treatment and disease burden included duration of suppressive antibiotics, number of invasive studies, pyelonephritis episodes, endoscopic treatments and open operations. All variables were varied spanning realistic ranges during sensitivity analyses to determine threshold values. RESULTS: The protocol of no antibiotics or followup imaging yielded the best cost-utility for vesicoureteral reflux grades II and III. Sensitivity analysis of variables spanning realistic ranges demonstrated that utility penalties for invasive imaging and outpatient pyelonephritis were particularly important in determining the highest utility protocols, with threshold values ranging from -0.5 to -0.8. CONCLUSIONS: In our models of treatment for vesicoureteral reflux a noninterventional approach constitutes the highest utility and least costly treatment for moderate grade reflux. Given the relative dearth of randomized trials, these analyses provide guidelines for current management of vesicoureteral reflux.

Algorithms↗
PubMed2003

The pathogenetic significance of deregulated signal transduction pathways in Hodgkin's disease: the NF-kappaB-AP-1 network.

In the recent years, progress has been made in defining the lineage origin of malignant cells of Hodgkin's disease. The use of single cell PCR analysis and of other molecular probes has allowed to determine that the malignant Hodgkin/Reed-Sternberg cells correspond mostly to a post germinal center stage of normal B-lymphocyte development. However, the agents which cause primary transformation events are still unknown. A comprehensive analysis of dysregulated signaling pathways in H/RS-cells with a focus on inducible and lymphoid-specific transcription factors has provided an independent approach to characterize molecular lesions, which may account for the tumorigenicity of H/RS-cells. Transcription factors of the NF-kappaB and AP-1 multigene families could be identified as crucial mediators of both, cell cycle promoting and cell-death inhibiting pathways in H/RS-cells. High level activity of these regulators has multifarious consequences for the gene expression repertoire of H/RS-cells, as has been revealed by large scale gene profiling. The dissection of the molecular mechanisms which constitutively activate NF-kappaB and AP-1 may help to gain further insight into the pathogenesis of Hodgkin's disease and may provide novel targets for pharmacological intervention.

Apoptosis↗
PubMed1989

[Investigation on calcifications in the breast].

This article reported the result of analysis of 96 cases with heaps of calcifications in the breast all verified by operation. The calcifications, according to the appearances on X-ray film were classified into 4 patterns: club-shaped, fine sandy, fragmented stonelike and coalescent. A comprehensive analysis was made in regard to spatial distribution and amount of calcification and the presence of a mass. The results indicated that club-shaped calcification is highly suggestive of malignancy regardless of the amount of calcification and the presence or absence of a mass. Simple fine sandy calcification in the absence of a mass can not differentiate benign from malignancy because of wide range of overlapping, whereas simple fragmented stone and coalescent types, according to the authors opinion denote benign.

Adenofibroma↗