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At least 1,783 records · Page 99Linked to original sources
PubMed2004

Cytogenetics in acute leukemia.

Cytogenetic analyses in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) have revealed a great number of non-random chromosome abnormalities. In many instances, molecular studies of these abnormalities identified specific genes implicated in the process of leukemogenesis. The more common chromosome aberrations have been associated with specific laboratory and clinical characteristics, and are now being used as diagnostic and prognostic markers guiding the clinician in selecting the most effective therapies. Specific chromosome aberrations and their molecular counterparts have been included in the World Health Organization classification of hematologic malignancies, and together with morphology, immunophenotype and clinical features are used to define distinct disease entities. However, the prognostic importance of less frequent recurrent aberrations in AML and ALL, both primary and secondary, is still to be determined. This review summarizes current views on clinical relevance of major cytogenetic findings in adult AML and ALL.

Adolescent↗
PubMedDate not supplied

A universal molecular descriptor system for prediction of logP, logS, logBB, and absorption.

Predictive models for octanol/water partition coefficient (logP), aqueous solubility (logS), blood-brain barrier (logBB), and human intestinal absorption (HIA) were built from a universal, generic molecular descriptor system, designed on the basis of atom type classification. The atom type classification tree was trained to optimize the logP predictions. With nine components, the final partial least-squares (PLS) model predicted logP of 10850 compounds in Starlist with a regression coefficient (r2) of 0.912, cross-validated r2 (q2) of 0.892, and root-mean-square error of estimation (RMSEE) of 0.50 log units. The PLS models for solubility (logS), blood-brain barrier (logBB), and a PLS-DA (discrimination analysis) model for HIA were established from the same atom type descriptors. The seven-component PLS model derived from a diverse set of 1478 organic compounds predicted a 21-compound test set designed by Yalkowsky with r2 = 0.88 and RMSEP (RMS error of prediction) = 0.64. A predictive r2 = 0.90 and RMSEE = 0.26 were achieved for logBB of a 57-compound "Abraham data set" with a three-component model. The first three components of a five-component PLS-DA model were sufficient to clearly separate the 169 drug molecules, collected by Abraham, into three classes, according to their percentage human intestinal absorption.

Absorption↗
PubMed2004

Rapid prediction of chemical metabolism by human UDP-glucuronosyltransferase isoforms using quantum chemical descriptors derived with the electronegativity equalization method.

This study aimed to evaluate in silico models based on quantum chemical (QC) descriptors derived using the electronegativity equalization method (EEM) and to assess the use of QC properties to predict chemical metabolism by human UDP-glucuronosyltransferase (UGT) isoforms. Various EEM-derived QC molecular descriptors were calculated for known UGT substrates and nonsubstrates. Classification models were developed using support vector machine and partial least squares discriminant analysis. In general, the most predictive models were generated with the support vector machine. Combining QC and 2D descriptors (from previous work) using a consensus approach resulted in a statistically significant improvement in predictivity (to 84%) over both the QC and 2D models and the other methods of combining the descriptors. EEM-derived QC descriptors were shown to be both highly predictive and computationally efficient. It is likely that EEM-derived QC properties will be generally useful for predicting ADMET and physicochemical properties during drug discovery.

Electricity↗
PubMed2006

Insights for human ether-a-go-go-related gene potassium channel inhibition using recursive partitioning and Kohonen and Sammon mapping techniques.

The human ether-a-go-go related gene (hERG) can be inhibited by marketed drugs, and this inhibition may lead to QT prolongation and possibly fatal cardiac arrhythmia. We have collated literature data for 99 diverse hERG inhibitors to generate Kohonen maps, Sammon maps, and recursive partitioning models. Our aim was to investigate whether these computational models could be used either individually or together in a consensus approach to predict the binding of a prospectively selected test set of 35 diverse molecules and at the same time to offer further insights into hERG inhibition. The recursive partitioning model provided a quantitative prediction, which was markedly improved when Tanimoto similarity was included as a filter to remove molecules from the test set that were too dissimilar to the training set (r2 = 0.83, Spearman rho = 0.75, p = 0.0003 for the 18 remaining molecules, >0.77 similarity). This model was also used to screen and prioritize a database of drugs, recovering several hERG inhibitors not used in model building. The mapping approaches used molecular descriptors required for hERG inhibition that were not reported previously and in particular highlighted the importance of molecular shape. The Sammon map model provided the best qualitative classification of the test set (95% correct) compared with the Kohonen map model (81% correct), and this result was also superior to the consensus approach. This study illustrates that patch clamping data from various literature sources can be combined to generate valid models of hERG inhibition for prospective predictions.

Binding, Competitive↗
PubMed1999

Clinical and morphological correlations for transglutaminase 1 gene mutations in autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a group of inherited disorders of cornification in which progress has recently been made in the identification of pathogenic mechanisms causing the disease. Transglutaminase 1 (TGM1) has been found as a defective gene in a large fraction of patients with lamellar ichthyosis (LI), a severe inherited scaling disorder of the skin. We have previously performed molecular genetic studies of 38Finnish ARCI families and found six different mutations in 13 families of 38 (34%). In this study we compared the molecular genetic alterations with clinical and electron microscopic findings of these patients. Families were classified by electron microscopy in ichthyosis congenita (IC) types I, II, III, IV and a non-defined group. TGM 1 gene mutation was found in all of the IC type II and 1/3 of the IC type 1 families. Although electron microscopy is not always used to classify ARCI patients, it can distinguish groups which are parallel with molecular genetic findings. This finding might be useful in the classification of ARCI patients for further linkage studies. Clinically typical phenotype of the TGM1 mutation carrier includes large, thick, brownish scales, but ichthyosis of some of these patients tends to be milder.

Adolescent↗
PubMed1999

Soft-tissue sarcomas: an update.

Despite their relative infrequency (which is often used as an excuse for poor treatment), soft-tissue sarcomas have been the focus of considerable interest and advances in recent years, mainly because of molecular genetic developments as well as evolution in their histological classification. In parallel, however, there remains no clear consensus regarding either the ideal biopsy technique (in this era of increasing outpatient management) or the best means of prognostication (particularly by histological grading). This review aims to discuss some of these recent developments and co-existent controversies. Aside from the understandable pursuit of modern biotechnological innovations, it seems that the most important goal remains the need to achieve more consistent primary surgical management of these tumours, preferably in specialist centres.

Biopsy↗
PubMed2004

Diagnosis of esophagogastric tumors.

Esophagogastric tumors occur in three sectors: the esophagus, the EG junction and the non-cardia stomach. Neoplasia develops in the squamous stratified epithelium of the esophagus and in the columnar epithelium of the Barrett's esophagus or in the stomach. At the junction, tumors arise either in a very short Barrett's esophagus or in the gastric epithelium of the cardia. The prognosis of tumors detected at the advanced stage is poor. Secondary prevention requires detection at the early stage. Most superficial neoplastic lesions in the esophagus and in the stomach have a non-protruding appearance, which is similar for premalignant and malignant lesions. Improved accuracy in endoscopic diagnosis and prediction of histology prior to biopsy and treatment decision is based upon magnification with a optical zoom and electronic processing of the captured image with structure enhancement, enhancement of the color of hemoglobin and narrow band imaging. This applies particularly to the exploration of the Barrett's esophagus for identification of the areas with intestinal metaplasia and of flat neoplastic areas. In spite of the predictive value of endoscopy for histology, biopsy samples are still required for pathology and eventually studies with biological markers. Spectroscopic techniques provide a new perspective, up to the level of molecular endoscopy, but they are unlikely to be cost/effective. The classification in the sub-types 0 of neoplastic lesions has some relevance to prediction of depth of invasion. In the esophagus, EUS staging with high frequency miniprobes is a useful complement.

Barrett Esophagus↗
PubMed2001

Proliferative activity of epidermal basal cells after wounding. AgNOR counts compared with bromodeoxyuridine reactivity in rats.

Quantitative changes in nucleolus organizer regions (NORs) are known markers of proliferation that can be demonstrated by a specific silver staining technique on paraffin-embedded sections. Wounding of skin induces proliferation of basal epidermal cells at the wound margin. The degree of proliferation depends on the survival time and can be measured by morphometric assessment of argyrophilic NORs (AgNORs). Following incision wounding of the pinnae, rats were allowed to survive for different intervals (7 rats per interval) up to 120 hours. Before each sacrifice, biopsies were taken and incubated in a bromodeoxyuridine (BrdU) solution, embedded in paraffin, and stained with an antibody against BrdU. At the same time morphometric analysis of AgNOR counts was performed on sections made from the same material. BrdU incorporating nuclei were assessed by simple counting, whereas morphometric analysis of AgNOR counts was computer aided. Both methods revealed an increase in the number of proliferating cells, a plateau phase being reached after about 36 hours, followed by a decline after about 70 hours. Both methods thus allowed a reliable temporal classification of the skin injury according to survival time. The molecular background of the AgNOR changes in relation to the proliferation of cellular elements is discussed in detail.

Animals↗
PubMed2002

Proposed criteria for classification of new genotypes of mumps virus.

The nucleotide sequences of a 300 bp segment carrying the small hydrophobic (SH) protein gene of a large number of virus strains, belonging to 10 different mumps virus genotypes denoted A-J, were compared. When virus strains belonging to the same genotype were compared intra-genotypically, a variation in the range 2-4% was recorded. The level of inter-genotypical variation was higher (8-18%). A consistent finding was the more pronounced variation found when the A genotype was compared to the B-J genotypes than when the B-J genotypes were compared among themselves. A similar relatively more pronounced genetic variation between the A and B-D genotypes has also been found previously with the hemagglutinin-neuraminidase and fusion protein genes. It is concluded that the establishment of a new genotype should be founded on a nucleotide variation of the SH gene of > or = 6% in relation to previously described genotypes.

Classification↗
PubMed2006

Sequence-based species delimitation for the DNA taxonomy of undescribed insects.

Cataloging the very large number of undescribed species of insects could be greatly accelerated by automated DNA based approaches, but procedures for large-scale species discovery from sequence data are currently lacking. Here, we use mitochondrial DNA variation to delimit species in a poorly known beetle radiation in the genus Rivacindela from arid Australia. Among 468 individuals sampled from 65 sites and multiple morphologically distinguishable types, sequence variation in three mtDNA genes (cytochrome oxidase subunit 1, cytochrome b, 16S ribosomal RNA) was strongly partitioned between 46 or 47 putative species identified with quantitative methods of species recognition based on fixed unique ("diagnostic") characters. The boundaries between groups were also recognizable from a striking increase in branching rate in clock-constrained calibrated trees. Models of stochastic lineage growth (Yule models) were combined with coalescence theory to develop a new likelihood method that determines the point of transition from species-level (speciation and extinction) to population-level (coalescence) evolutionary processes. Fitting the location of the switches from speciation to coalescent nodes on the ultrametric tree of Rivacindela produced a transition in branching rate occurring at 0.43 Mya, leading to an estimate of 48 putative species (confidence interval for the threshold ranging from 47 to 51 clusters within 2 logL units). Entities delimited in this way exhibited biological properties of traditionally defined species, showing coherence of geographic ranges, broad congruence with morphologically recognized species, and levels of sequence divergence typical for closely related species of insects. The finding of discontinuous evolutionary groupings that are readily apparent in patterns of sequence variation permits largely automated species delineation from DNA surveys of local communities as a scaffold for taxonomy in this poorly known insect group.

Animals↗
PubMed1999

Genomic signature: characterization and classification of species assessed by chaos game representation of sequences.

We explored DNA structures of genomes by means of a new tool derived from the "chaotic dynamical systems" theory (the so-called chaos game representation [CGR]), which allows the depiction of frequencies of oligonucleotides in the form of images. Using CGR, we observe that subsequences of a genome exhibit the main characteristics of the whole genome, attesting to the validity of the genomic signature concept. Base concentrations, stretches (runs of complementary bases or purines/pyrimidines), and patches (over- or underexpressed words of various lengths) are the main factors explaining the variability observed among sequences. The distance between images may be considered a measure of phylogenetic proximity. Eukaryotes and prokaryotes can be identified merely on the basis of their DNA structures.

Algorithms↗
PubMed2004

Update in management of head and neck sarcoma.

PURPOSE OF REVIEW: This update addressing head and neck sarcoma presents new data published after January 2003. This new information is presented following review of contemporary management principles established before 2003. RECENT FINDINGS: The application of advances in molecular and genetic techniques to characterize individual sarcomas has improved classification schemes and hopefully will lead to individually tailored therapy. Maturation and refinements of large tumor registries are permitting more detailed analysis of larger contemporary series of the rare head and neck sarcomas. Improved long-term survival of patients treated for sarcoma in their childhood has allowed study of the morbidity induced by treatment. Novel treatment strategies are under study to decrease morbidity without diminishing the chance for cure. SUMMARY: Progress in improving the treatment of sarcoma of the head and neck has been slow due to the lack of a large clinical experience with this rare neoplasm. Advances continue and are anticipated to be most striking in the study of genetic mechanisms.

Disease Management↗
PubMed2005

A continent of plant defense peptide diversity: cyclotides in Australian Hybanthus (Violaceae).

Cyclotides are plant-derived miniproteins that have the unusual features of a head-to-tail cyclized peptide backbone and a knotted arrangement of disulfide bonds. It had been postulated that they might be an especially large family of host defense agents, but this had not yet been tested by field data on cyclotide variation in wild plant populations. In this study, we sampled Australian Hybanthus (Violaceae) to gain an insight into the level of variation within populations, within species, and between species. A wealth of cyclotide diversity was discovered: at least 246 new cyclotides are present in the 11 species sampled, and 26 novel sequences were characterized. A new approach to the discovery of cyclotide sequences was developed based on the identification of a conserved sequence within a signal sequence in cyclotide precursors. The number of cyclotides in the Violaceae is now estimated to be >9000. Cyclotide physicochemical profiles were shown to be a useful taxonomic feature that reflected species and their morphological relationships. The novel sequences provided substantial insight into the tolerance of the cystine knot framework in cyclotides to amino acid substitutions and will facilitate protein engineering applications of this framework.

Amino Acid Sequence↗
PubMedDate not supplied

Aquaporins in plants.

Although very often exposed to a rapid changing environment, plants are in general unable to evade from unfavourable conditions. Therefore, a fine tuned adaptation of physiology including the water balance appears to be of crucial importance. As a consequence a relatively large number of aquaporin genes are present in plant genomes. So far aquaporins in plants were shown to be involved in root water uptake, reproduction or photosynthesis. Accordingly, plant aquaporin classification as simple water pores has changed corresponding to their molecular function into channels permeable for water, small solutes and/or gases. An adjustment of the respective physiological process could be achieved by regulation mechanisms, which range from post-translational modification, molecular trafficking to heteromerization of aquaporin isoforms. Here the function of the four plant aquaporin family subclasses with regard to substrate specificity, regulation and physiological relevance is described.

Ammonia↗
PubMed1996

Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. The hallmark of its pathology is the demyelinated plaque with reactive glial scar formation. However, a detailed analysis of the patterns of demyelination, oligodendroglia cell pathology and the reaction of other tissue components suggests that the pathogenesis of myelin destruction in this disease may be heterogeneous. In this review we present a new classification scheme of lesional activity on the basis of the molecular composition of myelin degradation products in macrophages. When these criteria are used, different patterns of demyelination can be distinguished, including demyelination with relative preservation of oligodendrocytes, myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination. Furthermore, in some cases a primary selective demyelination may be followed by a secondary oligodendrocyte loss in the established lesions. Finally, some extraordinarily severe conditions may result in destructive lesions with loss of myelin, oligodendrocytes, axons and astrocytes. This heterogeneity of plaque pathology is discussed in the context of recent experimental models of inflammatory demyelination, which show that different immunological pathways may lead to the formation of demyelinated plaques that reveal the diverse structural aspects described above. Our data indicate, that the demyelinated plaques of multiple sclerosis may reflect a common pathological end point of a variety of different immunological mechanisms of myelin destruction in this disease.

Animals↗
PubMed2005

characterization of acute-phase humoral immunity to monkeypox: use of immunoglobulin M enzyme-linked immunosorbent assay for detection of monkeypox infection during the 2003 North American outbreak.

A monkeypox outbreak occurred in the United States in 2003. Patient's sera were sent to the Centers for Disease Control and Prevention as a part of outbreak response measures. Clinical and epidemiologic information was abstracted from the case investigation forms. Serum samples from patients were tested by using an immunoglobulin M (IgM)-capture and an IgG enzyme-linked immunosorbent assay ELISA against Orthopoxvirus antigen. The detection of antiviral IgG and IgM antibodies and the kinetics of the antiviral IgG and IgM antibody responses were evaluated. Patients were classified as confirmed, probable, or suspect cases or were excluded as cases based on laboratory test results and epidemiologic and clinical criteria. A total of 37 confirmed case patients with monkeypox were identified, and 116 patients were excluded as case patients based on molecular testing or insufficient epidemiology and clinical data to warrant classification as a suspect or probable case. Of 37 confirmed case patients, 36 had a known history (presence or absence) of smallpox vaccination. Of those, 29 of the 36 either had or developed an IgG response, while 34 of the 36 developed an IgM response, regardless of vaccination status. Serum collected > or =5 days for IgM detection or serum collected > or =8 days after rash onset for IgG detection was most efficient for the detection of monkeypox virus infection. IgM ELISA detects recent infection with orthopoxviruses and, in this case, recent infection with monkeypox virus. In addition, analysis of paired sera for IgG and IgM detected seroconversion, another indicator of recent infection. The ELISA results correlated with the virologic PCR and viral culture results, indicating its diagnostic capabilities for monkeypox and potentially other orthopoxvirus infections due to zoonotic transmission or bioterrorism events.

Antibodies, Viral↗
PubMed2001

Leptospirosis.

Leptospirosis is a worldwide zoonotic infection with a much greater incidence in tropical regions and has now been identified as one of the emerging infectious diseases. The epidemiology of leptospirosis has been modified by changes in animal husbandry, climate, and human behavior. Resurgent interest in leptospirosis has resulted from large outbreaks that have received significant publicity. The development of simpler, rapid assays for diagnosis has been based largely on the recognition that early initiation of antibiotic therapy is important in acute disease but also on the need for assays which can be used more widely. In this review, the complex taxonomy of leptospires, previously based on serology and recently modified by a genotypic classification, is discussed, and the clinical and epidemiological value of molecular diagnosis and typing is also evaluated.

Animals↗