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At least 145 records · Page 8Linked to original sources
PubMedDate not supplied

[A proposal for a molecular genetic classification of the malformations of the nervous system].

OBJECTIVE: This proposal is a first attempt to incorporate the recent molecular genetic data that explains programming of development etiologically. DEVELOPMENT: Traditional schemes of classifying nervous system malformations are based upon descriptive morphogenesis of anatomical processes of ontogeny, such as neurulation, neuroblast migration and axonal pathfinding; such anatomical schemes do not allow for the incorporation of multiple genetic etiologies that lead to the same anatomical result, such as holoprosencephaly or lissencephaly. A scheme based purely on genetic mutations also is impractical because several genes might be involved sequentially in a cascade, the same genes serve different functions at different stages and are involved in multiple organ systems. Some complex malformations result from several unrelated defective genes, again citing the example of holoprosencephaly. Finally, a pure genetic classification would be too inflexible to incorporate anatomical criteria and also acquired lesions of the fetal brain that lead to secondary focal dysgeneses. The basis for the proposed scheme is, therefore, disturbances in patterns of genetic expression: polarity gradients of the axes of the neural tube (e.g. upregulation or downregulation of genetic influences); segmentation (e.g. deletions of specific neuromeres; ectopic expression); mutations that cause change in cell lineage (e.g. dysplastic gangliocytoma of cerebellum; myofiber differentiation within brain); and specific genes or molecules that mediate neuroblast migration in its early (e.g. filamin 1), middle (e.g. LIS1; doublecortin) or late course (e.g. reelin; L1 CAM). CONCLUSIONS: The classification schemes that served so well throughout the 20th century no longer are adequate for the 21st century. The proposed scheme undoubtedly will undergo many future revisions, but it provides a starting point using currently available data.

Humans↗
PubMedDate not supplied

Invariant classification of molecular views in electron micrographs.

Biological macromolecules can exhibit many different orientations in electron microscopical preparations. In particular in vitreous-ice-embedded specimens, the number of different views can be high. Existing techniques of analysis require the alignment of the molecular views relative to one or more reference images with cross-correlation ("matched filtering") techniques and are somewhat unsatisfactory because of the high noise level and the large number of different views in such images. We here propose a method in which first rotation-, translation- and mirror-invariant functions are derived from the large set of input images. These functions are subsequently classified automatically using multivariate statistical classification techniques. The different molecular views in the images can therewith be found without bias, provided that a statistically significant number of copies of the views are present in the data set. The basic ideas are exemplified with realistic model data.

Fourier Analysis↗
PubMed2004

Class discovery analysis of the lung cancer gene expression data.

Traditional histological classification of lung cancer subtypes is informative, but incomplete. Recent studies of gene expression suggest that molecular classification can be used for effective diagnostic and prediction of the treatment outcome. We attempt to build a molecular classification based on the public data available from a few independent sources. The data is reanalyzed with a new cluster analysis algorithm. This algorithm allows us to preserve the high dimensionality of data and produce the cluster structure without preliminary selection of significant genes or any other presumption about the relation between different cancer and normal tissue samples. The resulting clusters are generally consistent with the histological classification. However, our analysis reveals many additional details and subtypes of previously defined types of lung cancer. Large histological cancer types can be further divided into subclasses with different patterns of gene expression. These subtypes should be taken into account in diagnostics, drug testing, and treatment development for lung cancer patients.

Cluster Analysis↗
PubMed1998

Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology.

The classification of amyotrophic lateral sclerosis (ALS) is reconsidered in the light of developments in the molecular pathogenesis and histopathology of the condition. A current view is encapsulated in the El Escorial World Federation of Neurology criteria for the diagnosis of ALS. While intended for research purposes, use of these criteria for entry into clinical trials may result in the exclusion of some patient groups with related disorders that are likely to share aetiological mechanisms but which are not classified as 'definite ALS' or 'probable ALS'. The relationship between ALS and the more restricted motor disorders of progressive lateral sclerosis and progressive muscular atrophy, together with cerebral degenerations including ALS-dementia and ALS-related frontal lobe dementia, are reviewed. The possibility is raised that they all represent syndromic manifestations of a similar pathogenetic cascade whose clinical phenotype depends upon the anatomical selectivity of involvement in each individual. The new evidence regarding the central role of oxidative stress and abnormal glutamatergic neurotransmission in familial and sporadic ALS seem applicable across these disorders. New evidence regarding the molecular pathology of inclusion bodies in these various syndromes, including ubiquitinated inclusions and hyaline conglomerate inclusions, shows striking similarities between them. Marked differences in the anatomical distribution of lesions determine the predominance and type of motor and cognitive features in each syndrome. This concept of a clinicopathological spectrum is potentially of equal relevance to other late onset neurodegenerative disorders including multisystem atrophies, the Lewy body disorders and various manifestations of Alzheimer's disease. It will gain increasing importance as therapies evolve from the symptomatic to those directed at underlying pathogenetic events.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification.

Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. Histologically, endometrioid and mucinous carcinomas are considered type I, serous and clear cell carcinomas type II. Molecular data from multiple studies support the hypothesis of different genetic pathways in the development of endometrioid and serous carcinoma. The most frequent genetic alteration in endometrioid carcinoma is PTEN inactivation by mutation, followed by microsatellite instability (MIN) and mutations of K-ras and beta-catenin. PTEN and K-ras mutations and MIN are considered early events, occurring in a subset of atypical endometrial hyperplasia, whereas p53 mutation is considered a late event, during progression of about 10-20% of endometrioid carcinomas. In serous carcinoma, p53 mutation is the most frequent genetic alteration, followed by inactivation of p16 and e-cadherin and amplification of her2/neu. p53 mutation occurs in endometrial intraepithelial carcinoma, the putative precursor of serous carcinoma. Considering these genetic pathways, the current histological classification of endometrial carcinoma is molecular based.

Aging↗
PubMed2004

Clinical, genetic, and therapeutic insights into systemic mast cell disease.

PURPOSE OF REVIEW: Mast cell disease is markedly heterogeneous in its underlying molecular pathogenesis, clinical presentation, natural history, and specific treatment. Skin-only disease (cutaneous mastocytosis) is infrequent in adults and systemic mastocytosis may be broadly classified as an indolent or aggressive variant based on the absence or presence of impaired organ function. Urticaria pigmentosa and mast cell mediator release symptoms can occur in all categories of mast cell disease and may not be prognostically detrimental. The purpose of this review is to summarize current concepts and recent advances in the pathogenesis and treatment of adult mast cell disease. RECENT FINDINGS: A series of laboratory investigations has revealed that mast cell disease is a clonal stem cell disorder, and at least two genes (c-kit and PDGFRA) with pathogenetically relevant mutations have been identified. FIP1L1-PDGFRA+ mast cell disease responds completely to imatinib mesylate. Both Asp816Val c-kit+ and molecularly undefined cases have been shown to respond to 2-chlorodeoxyadenosine therapy after failing treatment with interferon-alpha. SUMMARY: A partial molecular classification of mast cell disease is now possible; Asp816Val c-kit+, FIP1L1-PDGFRA+, and molecularly undefined cases. Such molecular classification is therapeutically relevant.

Adult↗
PubMed2006

Histological classification and molecular genetics of meningiomas.

Meningiomas account for up to 30% of all primary intracranial tumours. They are histologically classified according to the World Health Organization (WHO) classification of tumours of the nervous system. Most meningiomas are benign lesions of WHO grade I, whereas some meningioma variants correspond with WHO grades II and III and are associated with a higher risk of recurrence and shorter survival times. Mutations in the NF2 gene and loss of chromosome 22q are the most common genetic alterations associated with the initiation of meningiomas. With increase in tumour grade, additional progression-associated molecular aberrations can be found; however, most of the relevant genes are yet to be identified. High-throughput techniques of global genome and transcriptome analyses and new meningioma models provide increasing insight into meningioma biology and will help to identify common pathogenic pathways that may be targeted by new therapeutic approaches.

Histological Techniques↗
PubMed2002

Quantification of telomerase activity, porphobilinogen deaminase and human telomerase reverse transcriptase mRNA in testicular tissue - new parameters for a molecular diagnostic classification of spermatogenesis disorders.

The aim of the study was to evaluate the quantitative detection of human telomerase reverse transcriptase (hTERT) mRNA and telomerase activity as new molecular diagnostic parameters for a subclassification of spermatogenesis disorders. Telomerase activity was detected by a quantitative telomerase PCR ELISA, and hTERT mRNA expression was quantified by fluorescence real-time RT-PCR in a LightCycler in cryopreserved testicular tissue specimens. This was paralleled by a histological workup. The discriminant analysis showed that detection of normalized hTERT expression was able to correctly classify 89.0% of the investigated tissue specimens into the subgroups of full spermatogenesis, maturation arrest or Sertoli-cell-only syndrome. In contrast, discriminant analysis revealed an only 58% accuracy of telomerase activity for the investigated tissue specimens. This study shows that the quantification of hTERT expression in testicular tissue by real-time fluorescence RT-PCR is well suited for correctly classifying spermatogenesis disorders and proved to be markedly superior to the determination of telomerase activity.

Biopsy↗
PubMed2006

Proteomic signatures corresponding to histological classification and grading of soft-tissue sarcomas.

We performed a global protein expression study on soft-tissue sarcoma in order to develop novel diagnostic biomarkers and allow molecular classification. 2-D difference gel electrophoresis was used to generate the global protein expression profiles of 80 soft-tissue sarcoma samples with seven different histological backgrounds. We found that 67 protein spots distinguished the subtypes of soft-tissue sarcoma. Hierarchical clustering with these 67 protein spots resulted in the grouping of all 80 sarcoma samples corresponding to the histological classification. We found that the expression pattern of tropomyosin isoforms was different in conventional and pleomorphic leiomyosarcomas. We also identified five proteins, including alpha-1-antitrypsin, alpha-actinin 1, HSP27, and elongation factor 2, that could differentiate between malignant fibrous histiocytomas and leiomyosarcomas in grade III into low-risk and high-risk groups, which differed significantly with respect to survival. These results establish proteomics as a powerful tool to develop novel biomarkers for diagnosis and molecular classification of soft-tissue sarcomas. Identification of proteins associated with survival in grade III sarcoma will allow delineation of a high-risk group that may benefit from adjuvant therapy and the exclusion of low-risk patients in whom additional therapies are unlikely to exhibit clinical benefit.

Biomarkers↗
PubMed2000

Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens.

Using Northern blotting, the expression levels of the genes for polyamine metabolism regulatory proteins and clusterin have been measured in a series of 23 human prostate cancers (CaPs) dissected from radical prostatectomy specimens. Patient matched, nontumor tissue was dissected from benign areas of the gland. The results indicate that transcripts encoding ornithine decarboxylase (ODC), ODC antizyme, adenosylmethionine decarboxylase, and spermidine/spermine N1-acetyltransferase (SSAT) were significantly higher, whereas clusterin (sulfated glycoprotein 2) mRNA was significantly lower in tumors compared with the benign tissue. All mRNA levels were compared with those of histone H3 and growth arrest-specific gene 1, markers of cell proliferation and cell quiescence, respectively, and glyceraldehyde 3-phosphate dehydrogenase, a housekeeping gene. In poorly differentiated and locally invasive CaPs and in tumors with unfavorable prognosis or total prostate-specific antigen (PSA) levels > 10.0 ng/ml at diagnosis, an overall increase in the levels of H3 mRNA and a decrease in growth arrest-specific gene 1 mRNA was detected, indicative of higher proliferation activity, whereas the differences in expression levels for the polyamine metabolism and clusterin genes were higher. ODC and SSAT changes were positively correlated in normal tissue but not in high-grade cancer, whereas ODC antizyme and SSAT changes were positively correlated in more malignant CaPs but not in normal tissue. Tumor classification based on the changes in expression levels of all of the genes studied could be correlated to differentiation grade and local invasiveness classification systems in 72.2 and 83.3% of the cases, respectively. In a 1-year follow-up period, three patients whose CaPs ranked as less aggressive according to clinical staging, but classified as advanced cancers with the proposed molecular classification, showed increases in total PSA levels, indicative of tumor relapse. Thus, molecular classification, based on gene expression, may enhance the available prognostic tools for prostate tumors.

Acetyltransferases↗
PubMed2000

Molecular genetic classification of central nervous system malformations.

Traditional schemes of classifying nervous system malformations are based on descriptive morphogenesis of anatomic processes of ontogenesis, such as neurulation, neuroblast migration, and axonal pathfinding. This proposal is a first attempt to incorporate the recent molecular genetic data that explain programming of development etiologically. A scheme based purely on genetic mutations would not be practical, in part because only in a few dysgeneses are the specific defects known, but also because several genes might be involved sequentially and many genes inhibit or augment the expression of others. The same genes serve different functions at different stages and are involved in multiple organ systems. Some complex malformations, such as holoprosencephaly, result from several unrelated defective genes. Finally, a pure genetic classification would be too inflexible to incorporate some anatomic criteria. The basis for the proposed scheme is, therefore, disturbances in patterns of genetic expression; polarity gradients of the axes of the neural tube (eg, upregulation or downregulation of genetic influences); segmentation (eg, deletions of specific neuromeres, ectopic expression); mutations that cause change in cell lineage (eg, dysplastic gangliocytoma of cerebellum, myofiber differentiation within brain); and specific genes or molecules that mediate neuroblast migration in its early (eg, filamin-1), middle (eg, LIS1, double-cortin), or late course (eg, reelin, L1-CAM). The proposed scheme undoubtedly will undergo many future revisions, but it provides a starting point using currently available data.

Central Nervous System↗
PubMedDate not supplied

Empirically derived classification of coagulation disorders in 224 patients.

BACKGROUND: It is not known whether the current molecular classification of blood coagulation disorders into severe (0-1%), moderate (1-5%) and mild (5-40% factor activity remaining) corresponds to the actual clinical situation or is in the patients best interest. METHODS: A questionnaire-based study of 244 patients. Principal factor analysis was used to create a set of variables for classification, which was performed using K-means algorithm. The main variables were use of prophylactic treatment during the last five years and during the last 12 months, home treatment, bleeding, surgery, antibody inhibitors, use of cold medication, pain, use of analgesics, functional disability and physical activity level. RESULTS: The first five variables of the main outcome measures loaded to a factor reflecting bleeding (bleeding factor) and the last four to a pain factor; both factors produced a 3-cluster solution with severe, moderate and mild bleeding or pain. Overlap between the molecular, bleeding and pain classifications was not extensive. Only 16% of 81 patients with severe coagulation factor deficiency had severe musculoskeletal pain and disability. Furthermore, only 28.6% of the patients with severe von Willebrand's disease actually had a severe bleeding disorder. CONCLUSIONS: Molecular classification does not correlate very well with the severity of disease as reflected in bleeding and pain. This is due to better prognosis for patients on modern medical management. Appropriate patient classification is a basis for defining and managing patients' clinical problems.

Adolescent↗
PubMed2000

The role of the pathologist as tissue refiner and data miner: the impact of functional genomics on the modern pathology laboratory and the critical roles of pathology informatics and bioinformatics.

This article provides an overview of how functional genomics is likely to impact on the pathology laboratory and highlights how informatics and tissue banking will greatly facilitate the molecular age of medicine. Important aspects of functional genomics in the post-genome era, including the roles of laser capture microdissection, DNA- and complementary DNA-based microarrays, proteomic methods, collaborative human tissue banking, tissue microarrays, and pathobioinformatics in the modern pathology laboratory are discussed. The role of mass spectroscopy in the analysis of RNA, DNA, and protein and its impact on the clinical laboratory, particularly in cost-effectiveness and time savings, are evaluated. This article explores how laboratory information systems (LISs) and the devices that feed them information may need to be modified to adapt to greater volumes of data for the new testing modalities that require understanding sophisticated fluorescence detection methods and image processing. Emerging genomic testing methods and their impact on pathology laboratory testing, especially in the area of molecular classification of neoplasms, are examined. The role of the tissue bank in the modern pathology laboratory as an archive of control normal tissues, as well as subsamples of the spectrum of progressive neoplastic states, is discussed in light of its critical importance to the molecular classification of cancer. Establishing a database that combines structured reports in pathology LISs and construction of tissue banking information systems will provide a rich resource for pathology departments. The article discusses a hypothetical resource, such as the Shared Tumor Expression Profiler, that would provide access to well-characterized tissue-based research resources for clinicians and researchers. Last, the article emphasizes how LISs can prepare for these changes, and how training pathologists in pathology informatics and bioinformatics (pathobioinformatics) is critical to ensure pathology's overall leadership role in the post-genome era.

Clinical Laboratory Techniques↗
PubMed2005

Molecular diagnosis. Classification, model selection and performance evaluation.

OBJECTIVES: We discuss supervised classification techniques applied to medical diagnosis based on gene expression profiles. Our focus lies on strategies of adaptive model selection to avoid overfitting in high-dimensional spaces. METHODS: We introduce likelihood-based methods, classification trees, support vector machines and regularized binary regression. For regularization by dimension reduction, we describe feature selection methods: feature filtering, feature shrinkage and wrapper approaches. In small sample-size situations efficient methods of data re-use are needed to assess the predictive power of a model. We discuss two issues in using cross-validation: the difference between in-loop and out-of-loop feature selection, and estimating model parameters in nested-loop cross-validation. RESULTS: Gene selection does not reduce the dimensionality of the model. Tuning parameters enable adaptive model selection. The feature selection bias is a common pitfall in performance evaluation. Model selection and performance evaluation can be combined by nested-loop cross-validation. CONCLUSIONS: Classification of microarrays is prone to overfitting. A rigorous and unbiased assessment of the predictive power of the model is a must.

Gene Expression Profiling↗
PubMed2003

Sequence diversity of mating-type genes in Phaeosphaeria avenaria.

Phaeosphaeria avenaria, one of the causal agents of stagonospora leaf blotch diseases in cereals, is composed of two subspecies, P. avenaria f. sp. triticea (Pat) and P. avenaria f. sp. avenaria (Paa). The Pat subspecies was grouped into Pat1-Pat3, based on restriction fragment length polymorphism (RFLP) and ribosomal DNA (rDNA) internal transcribed spacer (ITS) sequences in previous studies. Mating-type genes and their potential use in phylogeny and molecular classification were studied by DNA hybridization and PCR amplification. The majority of Pat1 isolates reported to be homothallic and producing sexual reproduction structures on cultural media had only the MAT1-1 gene. Minor sequence variations were found in the conserved region of MAT1-1 gene in Pat1 isolates. However, both mating-type genes, MAT1-1 and MAT1-2, were identified in P. avenaria isolates represented by ATCC12277 from oats (Paa) and the Pat2 isolates from foxtail barley ( Hordeum jubatum L.). Cluster analyses based on mating-type gene conserved regions revealed that cereal Phaeosphaeria is not phylogenetically closely related to other ascomycetes, including Mycosphaerella graminicola (anamorph Septoria tritici). The sequence diversity of mating-type genes in Pat and Paa supports our previous phylogenetic relationship and molecular classification based on RFLP fingerprinting and rDNA ITS sequences.

Ascomycota↗