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PubMed2002

Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology.

The following is a proposition for a simple histopathological classification system to measure inflammation in synovial tissue. This synovitis-score is employed in conventionally stained routine sections, and is applicable to every kind of synovitis, irrespective of etiology and including the following relevant morphological alterations. First: hyperplasia/enlargement of synovial lining cell layer. Second: activation of resident cells/synovial stroma. Third: inflammatory infiltration. All defined histopathological qualities are graded from absent (0), slight (1) and moderate (2) to strong (3), with summaries ranging from 0 to 9. 0 to 1 corresponds to no synovitis (inflammatory grade = 0), 2 to 3 to a slight synovitis (inflammatory grade 1), 4 to 6 to a moderate synovitis (inflammatory grade 2), and 7 to 9 to a strong synovitis (inflammatory grade 3). Using this score, we analyzed 308 random specimens of synovial tissue from degenerative (osteoarthritis (OA)) and inflammatory joint diseases - reactive arthritis (ReA), psoriasis arthritis (PA) and rheumatoid arthritis (RA) - as well as synovial tissue from healthy individuals. The mean grade given to synovitis of RA turned out to be significantly higher than the mean grade of OA (p < 0.0005) and of healthy controls (p < 0.0005). On the contrary, no significant differences could be found between the mean grades of synovitis scores from patients with RA and those with PA and ReA. Another comparison between RA-synovitis types I and II according to the Stiehl classification resulted in type I (p < 0.0005), showing significantly higher values of inflammatory infiltration, and type II (p = 0.037), showing significantly higher values of stroma activation. Since in OA, synovitis is regarded as a result of degenerative cartilage destruction whereas in inflammatory joint diseases (RA, PA, ReA), synovitis is regarded to be the cause of cartilage destruction, it can be concluded that scores with considerable high values indicate the pathogenetic potential of synovitis and that the inflammatory score may be helpful in estimating the destructive potential of synovitis at the same time. Furthermore, the comparison of the score data with the Stiehl RA-synovitis types shows that the score enables us to discriminate the morphological peculiarities of the synovitis types. In experimental pathology, it could provide standardized information on molecular synovial tissue analyses where a correlation of molecular with morphological data is essential. In diagnostic pathology, this synovitis score (in combination with other typing systems) could provide basic and standardized information concerning the degree of inflammatory alterations in synovial tissue.

Arthritis↗

PubMed2005

A quantum chemical and statistical study of ganoderic acids with cytotoxicity against tumor cell.

A set of molecular properties (variables) of 24 ganoderic acids with cytotoxicities against Meth-A tumor cells was calculated by the molecular orbital semi-empirical method AM1 and ChemPropStd. Pattern recognition techniques, principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to reduce dimensionality and investigate which subset of variables could be more effective for classifying the ganoderic acids according to their degree of cytotoxicities against tumor cells. The PCA and HCA studies showed that EHOMO (highest occupied molecular orbital energy), Mulliken electronegativity (chi), electronic energy (Eel), log P (octanol/water partition coefficient), and Connolly molecular area (MA) are the most important variables for the classification between the ganoderic acids with higher and lower cytotoxicities against tumor cells.

Acids↗

PubMed2004

Phylogeny of Veronica--a combination of molecular and chemical evidence.

A molecular phylogenetic tree of the genus Veronica, based on sequences of the ITS region of nuclear ribosomal DNA, provided a framework to test the use of iridoid chemical data in the classification of the genus. The distribution of ten iridoid glucosides, determined in 27 species of Veronica, supported the molecular results. The nine clades of the molecular tree appeared to correlate with a specific pattern of catalpol esters and chromosome base numbers. Some relationships within Veronica, previously suggested on the basis of morphological and karyological characters, were supported by our data. Neither the molecular, nor the chemical features were in favour of the classical circumscription and classification of the genus.

DNA, Ribosomal↗

PubMed2006

Karyology of the Antarctic scallop Adamussium colbecki, with some comments on the karyological evolution of pectinids.

Karyotype, location of the nucleolar organiser region (NOR) and heterochromatin presence and composition were studied in the Antarctic scallop Adamussium colbecki Smith, 1902. The karyotype exhibits 2n = 38 chromosomes with 11 pairs of metacentrics, 5 of submetacentrics, one subtelocentric and two telocentrics. Ag-NOR, CMA(3), DA/MM and NOR-FISH evidenced paracentromeric NORs on the short arm of 2nd pair chromosomes. Digestion with three restriction endonucleases followed by sequential staining with Giemsa, CMA(3) and DAPI evidenced on all chromosomes centromeric heterochromatin positive for both DAPI and CMA(3). In situ hybridisation analysis showed the presence of an AT-rich satellite DNA in the centromeric heterochromatin of several chromosomes. A mosaicism was detected in the germinal cell lines of one specimen, as in six of the 20 plates examined the set had 37 chromosomes with a missing pair of telocentrics and an unpaired metacentric. Comparison of the chromosome sets of all the pectinids studied to date and comparison with a phyletic tree obtained from molecular mitochondrial genes studies yielded good agreement between karyotype morphology and taxonomic classification.

Animals↗

PubMed1981

Metabolic actions of middle molecules.

About 20 inhibitory activities of middle molecular range were described and characterized sufficiently. The most useful classification divides them on the basis of their mobility on a column of Sephadex G-15. This classification enables us to compare the analytical and preparative data, the results of various laboratories and to suggest identity of various inhibitors. It is useful to outline the localization of the inhibitor action at the cellular level, to define the type of inhibitory activity and eventually to identify the second messenger of the action of inhibitor. The measurement of middle molecular (MM) fractions with various sophisticated methods has clearly established that there is a number of MM substances accumulating in biological fluids of patients with chronic renal failure. A part of them is probably of little clinical significance. However, those with biological activity may be of great clinical implication. To omit the interference of biologically inactive MM substances and to define the biological activity of those of clinical relevance the search turned to be biological actions of MM substances during the last years. The alteration such as impaired glucose utilization is chosen on the basis of clinical suggestion and the responsible inhibitor is looked for. This approach reflects in completely different strategy in comparison with the analytical search. Preparative instead of analytical arrangement is to be used. This does not mean only volume differences. The principles differ. This is to be stated to prevent inappropriate loss of time and effort of those starting to search in this manner.

Animals↗

PubMed2000

Classification of human ovarian tumors using multivariate data analysis of polypeptide expression patterns.

Large amounts of data on quantitative gene expression are generated by procedures such as 2-DE analysis of proteins or cDNA microarrays. Quantitative molecular variation may potentially be used for the development of methods for the classification of tumors. We used here the statistical concepts of principal components analysis (PCA) and partial least square analysis (PLS) in an attempt to type ovarian tumors. Using a set of 170 polypeptides, 22 tumors were used to establish a model ("learning set") for classification into 3 groups (benign/borderline/malignant). Eighteen tumors were then used to test the model. Six of 8 carcinomas and 3 of 4 borderline tumors were correctly classified. Two of 6 benign lesions were correctly classified, 3 were classified as borderline and 1 as carcinoma. We conclude that it may be possible to classify tumors according to their constitutive protein expression profile using multivariate analysis, thus making classification by artificial intelligence a future possibility.

Breast Neoplasms↗

PubMed2000

Classification of phase transitions in small systems

We present a classification scheme for phase transitions in finite systems like atomic and molecular clusters based on the Lee-Yang zeros in the complex temperature plane. In the limit of infinite particle numbers the scheme reduces to the Ehrenfest definition of phase transitions and gives the right critical indices. We apply this classification scheme to Bose-Einstein condensates in a harmonic trap as an example of a higher order phase transition in a finite system and to small Ar clusters.

Journal Article↗

PubMed2004

[Clinical and pathological significance of the genetic analysis in colorectal carcinomas].

The molecular genetics of colorectal carcinomas are among the best understood of common human cancers. Three inter-related molecular pathways are involved. The chromosomal instability pathway begins with inactivation of the APC/beta-catenin genes followed by activation of oncogenes and inactivation of additional suppressor genes, commonly with high frequency of allelic losses, cytogenetic abnormalities. The microsatellite instability pathway begins with inactivating one of a group of genes responsible for DNA nucleotide mismatch repair leading to extensive mutations in both repetitive and non-repetitive DNA sequences with low frequencies of allelic losses and rare alteration of tumor DNA content. Finally, the CpG island methylation pathway involves inactivation of genes by methylation of cytosines in promoter regions to silence gene expression without DNA sequence alterations. Molecular genetics have the potential for clinical applications. Combination of genetic classification of high levels of microsatellite instability (MSI-H), gene expression analysis of mismatch repair genes and subsequent mutation analysis of inactivated genes can be used as an effective method for the identification of hereditary nonpolyposis colorectal carcinoma patients. Molecular genetic alterations have been proposed to be of prognostic value, including allelic deletion on chromosome 18q, and on chromosome 17p. MSI-H has been reported as a marker for better prognosis. Individualizing chemoradiation by use of predictive markers for response or resistance to therapy is important in patients with advanced disease or candidacy for adjuvant therapy.

Chromosomal Instability↗

PubMed1997

Early emergence of three dopamine D1 receptor subtypes in vertebrates. Molecular phylogenetic, pharmacological, and functional criteria defining D1A, D1B, and D1C receptors in European eel Anguilla anguilla.

The existence of dopamine D1C and D1D receptors in Xenopus and chicken, respectively, challenged the established duality (D1A and D1B) of the dopamine D1 receptor class in vertebrates. To ascertain the molecular diversity of this gene family in early diverging vertebrates, we isolated four receptor-encoding sequences from the European eel Anguilla anguilla. Molecular phylogeny assigned two receptor sequences (D1A1 and D1A2) to the D1A subtype, and a third receptor to the D1B subtype. Additional sequence was orthologous to the Xenopus D1C receptor and to several other previously unclassified fish D1-like receptors. When expressed in COS-7 cells, eel D1A and D1B receptors display affinity profiles for dopaminergic ligands similar to those of other known vertebrate homologues. The D1C receptor exhibits pharmacological characteristics virtually identical to its Xenopus homologue. Functionally, while all eel D1 receptors stimulate adenylate cyclase, the eel D1B receptor exhibits greater constitutive activity than either D1A or D1C receptors. Semiquantitative reverse transcription-polymerase chain reaction reveals the differential distribution of D1A1, D1A2, D1B, and D1C receptor mRNA within the hypothalamic-pituitary axis of the eel brain. Taken together, these data suggest that the D1A, D1B, and D1C receptors arose prior to the evolutionary divergence of fish and tetrapods and exhibit molecular, pharmacological, and functional attributes that unambiguously allow for their classification as distinct D1 receptor subtypes in the vertebrate phylum.

Adenylyl Cyclases↗

PubMed2001

[Clinical genetics at the crossroads: the example of hereditary kidney diseases].

Clinical genetics has reached a crossroads. Indeed recent progress in molecular genetics has generated great hope. This progress has consequences beyond genetic diseases, leading to the understanding of much more general mechanisms of disease. This progress has also permitted a better classification of genetic entities, such as Alport's syndrome, based on the molecular mechanisms involved. Lastly this progress allows us to design pharmacologic therapeutic approaches. Enzyme replacement therapy in Fabry's disease is a recent example of this approach. Difficulties are much greater in diseases such as autosomal dominant polycystic kidney disease. To reach these goals, height collaboration between molecular genetics and cell biology in the post-gene era, and between clinical genetics and other medical specialties, is required not only in the field of pediatric diseases, but also in late-onset genetic diseases.

Genetics, Medical↗

PubMed2026

Guidelines for Genetic Testing of Peripheral Nerve Disorders.

Inherited peripheral neuropathies (IPNs) comprise a clinically and genetically heterogeneous group of disorders affecting approximately 1 in 2500 individuals and represent one of the most common inherited neurologic diseases. The rapidly expanding identification of disease-causing genes and the widespread implementation of next-generation sequencing (NGS) have fundamentally transformed the diagnostic evaluation of these disorders. Contemporary molecular testing has substantially increased diagnostic yield, shortened the diagnostic delay, refined disease classification, and strengthened genotype-phenotype correlations. In the United States, NGS-based multigene panels have become the most cost-effective first-line molecular diagnostic approach for most patients with suspected inherited neuropathies, whereas phenotype-directed single-gene testing remains appropriate in selected clinical circumstances and in healthcare systems in which access to comprehensive sequencing is limited. Despite these advances, challenges continue to affect diagnostic accuracy, including interpretation of variants of uncertain significance, detection of copy number variants and repeat expansions, technical limitations associated with highly homologous genomic regions such as SORD, and variability in gene content and analytic performance among commercially available testing platforms. Accurate diagnosis therefore requires integration of clinical phenotype, electrodiagnostic findings, family history, and molecular data. Establishing a precise genetic diagnosis has become increasingly important because it improves prognostic accuracy, guides genetic counseling and cascade testing, identifies patients with treatable hereditary neuropathies such as transthyretin amyloidosis, and facilitates enrollment in gene-specific clinical trials and emerging precision therapies. An evidence-based, phenotype-driven approach that incorporates contemporary molecular technologies is essential to maximize diagnostic efficiency while recognizing the strengths and limitations of currently available genetic testing strategies.

Charcot–Marie–tooth disease↗

PubMed2003

A molecular perspective on corneal dystrophies.

Corneal dystrophies refer to a group of corneal diseases and that are genetically determined. These have been traditionally classified with respect to the layer of cornea involved. We now know that this does not reflect the underlying pathobiology. Most of the corneal dystrophies are of Mendelian inheritance with some phenotype diversity and a variable degree of penetrance. The dystrophies involving enzymatic processes tend to be of autosomal recessive inheritance. In some cases, such as keratoconus, the inheritance pattern is not always clear and is considered complex. The age of onset of the disease, as in most inherited eye disorders, is variable and does not reflect the underlying pathogenic defect. Few cases are congenital. Our understanding of corneal dystrophies is undergoing somewhat of a revolution as over 12 chromosomes have been associated with corneal dystrophies with mutations identified in at least 14 genes if one includes anterior segment dysgenesis in this group of conditions. Several dystrophies remain without a gene or a genetic location (locus) and more familial studies are required. The new molecular information is challenging the traditional thinking about these conditions that was usually guided by the histopathological findings. As this new knowledge becomes more refined, the classification of this group of disorders will eventually be revisited to have a molecular basis. The elucidation of the underlying biochemical pathways may allow us to envisage the possibility of modulating these phenotypes in the future.

Corneal Dystrophies, Hereditary↗

PubMed2002

Thomas Kuhn is alive and well: the evolutionary relationships of simple life form--a paradigm under siege ?

A Kuhnian framework is used to analyze the current controversy over whether two or three fundamental types of life forms exist. Until the 1980s, all life was classified into two primary forms: eukaryotes and prokaryotes. Using molecular sequencing data, Carl Woese suggested the archaebacteria constituted a third domain. In the mid-1990s, Radhey S. Gupta challenged the three-domain hypothesis. While this dispute may seem to be a purely technical debate over the analysis of protein and nucleic acid sequence data, the controversy encompasses broader issues such as the aims of classification and the role of microorganisms in the biosphere. At the heart of this dispute is what kinds of data are relevant to constructing an overall taxonomy. The prestige of molecular biology played a large role in why the three-domain hypothesis was accepted so readily, but supporters of the two-domain hypothesis argue that the fossil record, morphology, and cell physiology should all play a role in taxonomy. This case study provides a good example of a paradigm shift in the making, demonstrating that issues beyond the raw data will be significant factors in deciding whether the three-domain hypothesis will prevail or a new classificatory scheme will emerge.

Animals↗

PubMed2006

Pathology and molecular biology of gastric cancer.

Several attempts to classify gastric cancer (GCA) have been made over the past decades. Most successful, and widely used, is the classification by Laurén, which distinguishes, by microscopical morphology alone, two main cancer pathogeneses, diffuse (DGCA) and intestinal (IGCA) subtypes, which appear clearly as dissimilar clinical and epidemiological entities. Here we review the main differences in epidemiology, histopathology, and molecular pathology of the two main subtypes of gastric carcinomas based on Laurén classification. In clinical practice, however, clinical staging, particularly in predicting the survival, still remains superior to all classifications of gastric cancer independent of cancer type. The existence of local precursor lesions or conditions of IGCA tumours, i.e. Helicobacter pylori gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), adenoma, dysplasia, and intramucosal neoplasia, is firmly established. The links of DGCA with intestinal-type epithelium, AG or IM are poor, or do not exist. So far, H. pylori gastritis is the only universal precursor condition for DGCA. It implies that AG and achlorhydria are of minor significance and infrequent in the development of DGCA but are important steps in that of IGCA. Despite an increasing body of data, the overall view on molecular pathology of GCA remains fragmentary. No consistent differences in the molecular pathology of GCA subtypes to meet the Laurén classification have been established. With the exception of TP53, no gene mutation occurring regularly in both histological types of GCA has been reported. Chromosomal aberrations and loss of heterozygosity seem to be non-specific and do not follow any consistent route in the progression of GCA. Microsatellite instability is more commonly found in IGCA than in DGCA. The present epigenetic data suggest that most of the decrease (or loss) of gene expression may be explained by promoter hypermethylation which is more often found in IGCA. In DGCA specific genes such as CDH1 are more often hypermethylated. Compared with GCA, in premalignant condition lesions gene mutations and chromosomal aberrations are infrequent. Epigenetic dysregulation might also represent a major mechanism for altered gene expression in premalignant stages in gastric carcinogenesis.

Biomarkers, Tumor↗

PubMed2004

Acute leukemia subclassification: a marker protein expression perspective.

Improved leukemia classification and tailoring of therapy have greatly improved patient outcome particularly for children with acute leukemia (AL). Using immunophenotyping, molecular genetics and cytogenetics the low hanging fruits of biomedical research have been successfully incorporated in routine diagnosis of leukemia subclasses. Future improvements in the classification and understanding of leukemia biology will very likely be more slow and laborious. Recently, gene expression profiling has provided a framework for the global molecular analysis of hematological cancers, and high throughput proteomic analysis of leukemia samples is on the way. Here we consider classification of acute leukemia samples by flow cytometry using the marker proteins of immunophenotyping as a component of the proteome. Marker protein expressions are converted into quantitative expression values and subjected to computational analysis. Quantitative multivariate analysis from panels of marker proteins has demonstrated that marker protein expression profiles can distinguish MLLre from non-MLLre ALL cases and also allow to specifically distinguish MLL/AF4 cases. Potentially, these quantitative expression analyses can be used in clinical diagnosis. Immunophenotypic data collection using flow cytometry is a fast and relatively easily accessible technology that has already been implemented in most centers for leukemia diagnosis and the translation into quantitative expression data sets is a matter of flow cytometer settings and output calibration. However, before application in clinical diagnostics can occur it is crucial that quantitative immunophenotypic data set analysis is validated in independent experiments and in large data sets.

Acute Disease↗

PubMed2003

Molecular genetics of pediatric soft tissue tumors: clinical application.

The application of molecular genetics to pediatric soft tissue tumors has grown tremendously over the last decade. It has resulted in the identification of novel genes that have provided us with an increased understanding of oncogenesis. Furthermore, these findings have identified diagnostic and potentially prognostic factors for patient management. Molecular diagnostic techniques, such as reverse transcription PCR (RT-PCR) and fluorescence in situ hybridization (FISH), have become important tools for evaluating pediatric soft tissue tumors. By detecting characteristic fusion genes, these techniques have greatly increased the diagnostic accuracy of histopathological classification. One of the exciting promises of the development of these molecular techniques is their ability to detect micrometastasis and minimal residual disease. Monitoring of minimal residual disease in pediatric soft tissue tumors by quantitative RT-PCR may provide important prognostic information. Furthermore, the potential development of targeted therapy based on the understanding of the molecular pathology of a specific soft tissue tumor may complement existing treatments and improve disease outcome.

Child↗

PubMed1992

[A new system of diagnosis and classification--malignant lymphoma].

Malignant lymphoma is usually divided into Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) according to biological characteristics. Malignant lymphoma in Japan has such the characteristics as few incidence of HD, which is usually favorable in prognosis, and high incidence of NHLs, which have further distinctive features of less incidence of favorable follicular B cell lymphoma and of higher incidence of unfavorable diffuse T cell lymphoma including adult T cell leukemia/lymphoma (ATLL) in comparison with those in western countries. As a recent trend of progress in lymphoma diagnosis an introduction of immunological and molecular biological techniques has given an impact to the previous classification of malignant lymphoma based mainly on morphological criteria. Nowadays, the classification of pathologic type in HD seems to be settled in Rye classification. On the other hand in NHL the LSG classification has been well fixed in Japan and Working Formulation originated in USA has been well used internationally after a historical confusion. In this article a present state of working classification in malignant lymphoma is briefly described and discussed.

Hodgkin Disease↗

PubMed2003

Molecular plasticity of human melanoma cells.

The molecular analysis of tumors, such as melanoma, has benefited significantly from microarray technology that can facilitate the classification of tumors based on the differential expression of genes. The data summarized in this review describe the molecular profile of aggressive cutaneous and uveal melanoma cells as that of multiple phenotypes similar to a pluripotent, embryonic-like stem cell. A noteworthy example of the plasticity of the aggressive melanoma cell phenotype is demonstrated by the ability of these tumor cells to engage in vasculogenic mimicry and neovascularization. A review of the current evidence demonstrating important cellular and molecular determinants of melanoma vasculogenic mimicry is presented. In addition, novel signaling pathways are discussed, involving VE-cadherin, EphA2, FAK, and PI 3-kinase, which promote cell migration, invasion, and matrix remodeling. The observations summarized in this review describe some of the key molecular events that regulate the process of melanoma vasculogenic mimicry and identify new signal transduction pathways that can serve as putative targets for therapeutic intervention.

Antigens, CD↗