[Molecular galenics. 11. Influence of pressure on the classification degree of cellulose powders].
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Cellulose↗
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Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification.
This review addresses the genetic mutations and cell signaling pathway alterations in colorectal premalignant polyps, focusing on the link between molecular changes and morphologic features. Biallelic APC (adenomatous polyposis coli) mutations are directly responsible for the specific and characteristic cytologic features of dysplastic cells in conventional tubular adenomas. Sessile serrated adenomas (SSAs) are the precursor lesions of the serrated neoplasia pathway. The BRAF activating mutation and hypermethylation of SLC5A8, which mediates short chain fatty acid transport, may be the important events in the genesis of SSAs. Intracellular butyrate inhibits histone deacetylase, allowing histone hyperacetylation and, eventually, transcriptional activation of specific genes. Decreased p21(WAF1/CIP1) and activation of the mitogen-activated protein kinase pathway may be the key intermediary alterations. Progressive loss of cell cycle control and decreased and altered cytoplasmic differentiation produce the characteristic constellation of morphologic changes of SSAs and traditional serrated adenomas.
Adaptor Proteins, Signal Transducing↗
Molecular genetics and its application to the diagnosis and classification of hematopoietic neoplasms.
Diagnostic pathology and hematology have been enormously helped by recent advances in laboratory techniques that enable sensitive detection and more accurate and reproducible classification of lymphoproliferative processes. This review will focus on the normal molecular mechanisms that lead to the generation of immunocompetence. In addition, some of the techniques of recombinant DNA technology that can be applied to the diagnosis and classification of hematopoietic neoplasms will be described. These common DNA techniques can be of great help in the following problems: differentiation of monoclonal (usually malignant) from polyclonal (usually benign) processes, assistance in differentiation of malignant hematopoietic neoplasms from other poorly differentiated malignant neoplasms of nonhematopoietic lineage such as melanoma or carcinoma, determination of cell lineage (i.e., T lymphocyte versus B lymphocyte), and identification of cytogenetic abnormalities such as chromosomal translocations. From these cytogenetic abnormalities probes may be constructed and used to substitute for the more labor-intensive, technically demanding conventional microscopic karyotype.
Genetic Techniques↗
Genomics in myeloid leukemias: an array of possibilities.
Myeloid leukemias are clonal hematopoietic stem cell disorders characterized either by proliferation of one or more of the myeloid lineages (chronic myelogenous leukemia) or by clonal expansion of myeloid blasts (acute myeloid leukemia). Over the past several years our knowledge of these hematologic malignancies has increased tremendously. The result is a classification that incorporates morphologic, immunophenotypic, genetic and clinical features in an attempt to define biologically and clinically relevant entities. Nevertheless, in many tumor subtypes the pathogenic event is still unknown. Furthermore, well-defined leukemia subgroups exhibit considerable heterogeneity, arousing the suspicion that several molecularly distinct subtypes might exist within the same cytogenetic category. Therefore, an ideal classification system would ultimately be based on the underlying molecular pathogenesis, but such knowledge is not yet available. However, by surveying the expression levels of thousands of genes in parallel, DNA microarrays have recently contributed to an increasingly refined molecular taxonomy of myeloid disorders. This powerful technology is becoming well established and has been used to diagnosis cancer and predict clinical outcome, to discover novel tumor subclasses, to gain insights into pathogenesis, and to identify new therapeutic targets. While many challenges remain ahead, genomic technologies have already demonstrated tremendous potential. We expect whole genome approaches will significantly contribute to a better understanding of the pathogenesis and result in a refined molecular classification of myeloid leukemias.
Gene Expression Profiling↗
The inherited palmoplantar keratodermas.
The inherited palmoplantar keratodermas (PPK) constitute a complex heterogeneous group of genodermatoses, which are difficult to classify clinically. The application of modern molecular biology techniques are leading to an increased understanding of the genetic bases of these disorders and are paving the way towards a classification based upon molecular pathology. We review the recent research advances in this field and the implications for development of novel approaches to disease management.
Humans↗
Gastrointestinal stromal tumours: an update.
Recently, there has been intense interest in the study of gastrointestinal stromal tumour (GIST); one might call it a virtual GIST revolution. This is due largely to the realization that most GISTs express KIT and harbour activating c-KIT (KIT) or platelet-derived growth factor receptor-alpha (PDGFRA) receptor tyrosine kinase mutations that can be targeted by small molecule pharmacological inhibitors. Pathologists have benefited greatly from this revolution, mainly in the form of an improved ability to classify GISTs and, even more recently, in understanding the molecular underpinnings that underlie many fascinating clinical and pathological correlations. It is the purpose of this review to summarize recent developments in GIST classification and the molecular pathogenesis of GIST.
Gastrointestinal Stromal Tumors↗
Long-term disease-free acute promyelocytic leukemia patients really can be cured at molecular level.
The characteristic t(15;17) translocation involving chromosomes 15 and 17 is specifically associated with both the common and the variant subtypes of acute promyelocytic leukemia (APL) (M3 according to FAB classification). At the molecular level, it fuses genes encoding PML on chromosome 15 and the nuclear retinoic acid receptor-alpha (RAR alpha) on chromosome 17. The subsequent expression of PML/RAR alpha fusion mRNA provides a potential molecular marker that can be detected in leukemic cells taken from patients with APL. Using PML and RARa sequence specific primers, reverse transcription-polymerase chain reaction (RT-PCR) assays have been developed for detection of PML/RAR alpha transcript in leukemic cells obtained from patients; these RT-PCR assays are more sensitive than conventional cytogenetic analysis.
Adolescent↗
Expression of alpha 1-adrenergic receptor subtype mRNA in rat tissues and human SK-N-MC neuronal cells: implications for alpha 1-adrenergic receptor subtype classification.
At least three subtypes of alpha 1-adrenergic receptors (alpha 1ARs) have been identified using molecular techniques (alpha 1a/d, alpha 1b, and alpha 1c), whereas two subtypes of alpha 1ARs have been identified pharmacologically (alpha 1A and alpha 1B); however, controversies exist regarding how these two classification schemes relate to each other. In an attempt to clarify some of the controversies regarding classification of alpha 1AR subtypes, we have re-evaluated the distribution of mRNA for the cloned alpha 1AR subtypes (alpha 1a/d, alpha 1b, and alpha 1c) in various rat tissues thought to express alpha 1AR subtypes, as well as the human neuronal cell line SK-N-MC (a recently described model for pharmacologically defined alpha 1AAR and alpha 1BAR subtypes), using sensitive ribonuclease protection assay techniques. Total RNA extracted from various rat tissues and SK-N-MC cells was hybridized with rat and human alpha 1AR subtype-specific probes, respectively. In contrast to previously reported Northern blot analyses, alpha 1cAR mRNA is expressed in many rat tissues. Expression of alpha 1cAR mRNA is highest in those tissues that have been previously characterized by radioligand binding as expressing the classical, pharmacologically defined alpha 1AAR. Likewise, the human neuronal SK-N-MC cell line, classically thought to express pharmacological alpha 1AAR and alpha 1BAR subtypes, expresses both alpha 1a/dAR and alpha 1cAR mRNA and no alpha 1bAR mRNA. Collectively, these data suggest that the cloned alpha 1cAR subtype may represent the pharmacological alpha 1AAR, and they have important implications for merging pharmacological and molecular classifications of alpha 1AR subtypes.
Animals↗
PCA disjoint models for multiclass cancer analysis using gene expression data.
MOTIVATION: Microarray expression profiling appears particularly promising for a deeper understanding of cancer biology and to identify molecular signatures supporting the histological classification schemes of neoplastic specimens. However, molecular diagnostics based on microarray data presents major challenges due to the overwhelming number of variables and the complex, multiclass nature of tumor samples. Thus, the development of marker selection methods, that allow the identification of those genes that are most likely to confer high classification accuracy of multiple tumor types, and of multiclass classification schemes is of paramount importance. RESULTS: A computational procedure for marker identification and for classification of multiclass gene expression data through the application of disjoint principal component models is described. The identified features represent a rational and dimensionally reduced base for understanding the basic biology of diseases, defining targets for therapeutic intervention, and developing diagnostic tools for the identification and classification of multiple pathological states. The method has been tested on different microarray data sets obtained from various human tumor samples. The results demonstrate that this procedure allows the identification of specific phenotype markers and can classify previously unseen instances in the presence of multiple classes.
Acute Disease↗
The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system.
BACKGROUND: The objective of this study was to compare the accuracy of disease progression prediction of the molecular genetics and morphometry-based Endometrial Intraepithelial Neoplasia (EIN) and World Health Organization 1994 (WHO94) classification systems in patients with endometrial hyperplasias. METHODS: A multicenter, multivariate analysis was conducted on 477 patients with endometrial hyperplasia who were required to have a 1-year minimum disease-free interval from the time of the index biopsy (1-18 years of follow-up). The results from that analysis were compared with the results from 197 patients who had < 1 year of follow-up. RESULTS: Twenty-four of 477 hyperplasias (5.0%) progressed to malignant disease over an average of 4 years (maximum, 10 years). According to the WHO94 classification, 16 of 123 atypical hyperplasias (13%) and 8 of 354 nonatypical hyperplasias (2.3%) progressed (hazard ratio [HR] = 7). Twenty-two of 118 EINs (19%) and 2 of 359 non-EINs (0.6%) progressed (HR = 45). EIN was prognostic within each WHO94 subcategory. Progression rates were 3% in simple hyperplasias, 22% in complex hyperplasias, 17% in simple atypical hyperplasias, and 38% in complex atypical hyperplasias with EIN, compared with progression rates of 0.0-2.0% in all hyperplasias if EIN was absent. EIN detected precancerous lesions (sensitivity, 92%) better than WHO94 atypical hyperplasias collectively (67%) or complex atypical hyperplasias alone (46%). In a Cox regression analysis, EIN was the strongest prognostic index of future endometrial carcinoma. The same was true for patients with < 1 year of follow-up (HR for EIN, atypical hyperplasia, and complex atypical hyperplasia: 58, 7, and 8, respectively). CONCLUSIONS: The EIN classification system predicted disease progression more accurately than the WHO94 classification and identified many women with benign changes that would have been regarded as high risk according to the WHO94 classification system.
Adult↗
Molecular descriptors influencing melting point and their role in classification of solid drugs.
The aim of the study was to investigate whether easily and rapidly calculated 2D and 3D molecular descriptors could predict the melting point of drug-like compounds, to allow a melting point classification of solid drugs. The melting points for 277 structurally diverse model drugs were extracted from the 12th edition of the Merck Index. 2D descriptors mainly representing electrotopology and electron accessibilities were calculated by Molconn-Z and the AstraZeneca in-house program Selma. 3D descriptors for molecular surface areas were generated using the programs MacroModel and Marea. Correlations between the calculated descriptors and the melting point values were established with partial least squares projection to latent structures (PLS) using training and test sets. Three different descriptor matrixes were studied, and the models obtained were used for consensus modeling. The calculated properties were shown to explain 63% of the melting point. Descriptors for hydrophilicity, polarity, partial atom charge, and molecular rigidity were found to be positively correlated with melting point, whereas nonpolar atoms and high flexibility within the molecule were negatively correlated to this solid-state characteristic. Moreover, the studied descriptors were successful in providing a qualitative ranking of compounds into classes displaying a low, intermediate, or high melting point. Finally, a mechanism for the relation between the molecular descriptors and their effect on the melting point and the aqueous solubility was proposed.
Chemistry, Physical↗
Inherited prion disease with 144 base pair gene insertion. 2. Clinical and pathological features.
A large family with autosomal dominant segregation of presenile dementia, and other neurological and behavioural features is described. At various times, family members have carried diagnoses of Alzheimer's disease, Huntington's disease, Parkinson's disease, myoclonic epilepsy, atypical dementia, Pick's disease, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Molecular genetic studies have enabled classification of this disease at the molecular level as one of the group of inherited prion diseases. Here we describe the phenotype of inherited prion disease (PrP 144 bp insertion).
Adult↗
Effect of molecular descriptor feature selection in support vector machine classification of pharmacokinetic and toxicological properties of chemical agents.
Statistical-learning methods have been developed for facilitating the prediction of pharmacokinetic and toxicological properties of chemical agents. These methods employ a variety of molecular descriptors to characterize structural and physicochemical properties of molecules. Some of these descriptors are specifically designed for the study of a particular type of properties or agents, and their use for other properties or agents might generate noise and affect the prediction accuracy of a statistical learning system. This work examines to what extent the reduction of this noise can improve the prediction accuracy of a statistical learning system. A feature selection method, recursive feature elimination (RFE), is used to automatically select molecular descriptors for support vector machines (SVM) prediction of P-glycoprotein substrates (P-gp), human intestinal absorption of molecules (HIA), and agents that cause torsades de pointes (TdP), a rare but serious side effect. RFE significantly reduces the number of descriptors for each of these properties thereby increasing the computational speed for their classification. The SVM prediction accuracies of P-gp and HIA are substantially increased and that of TdP remains unchanged by RFE. These prediction accuracies are comparable to those of earlier studies derived from a selective set of descriptors. Our study suggests that molecular feature selection is useful for improving the speed and, in some cases, the accuracy of statistical learning methods for the prediction of pharmacokinetic and toxicological properties of chemical agents.
Algorithms↗
Use of amoB as a new molecular marker for ammonia-oxidizing bacteria.
Specific molecular determination and classification of ammonia-oxidizing bacteria have relied on the use of conventional markers such as 16S rDNA. However, this gene does not satisfactorily provide a wide vision of all phylogenetic lineages. Despite the initial expectations, the use of functional genes as for example amoA has only been useful to corroborate the established taxonomy. Ammonia-oxidizing bacteria constitute a physiological group that crosses over principal phylogenetic radiations. Therefore, it is necessary to look for novel functional markers, which are needed for both diversity and taxonomic studies. In this work, the available amoB sequences have been used to design a new degenerate set of primers flanking a ca. 500-bp region. Partial amoB gene sequences of up to 16 AOB strains (5 Nitrosomonas, 10 Nitrosospira, and 1 Nitrosococcus) belonging to both the beta- and the gamma-Proteobacteria have been obtained. Comparison of both DNA and deduced amino acid sequences results in three subgroups, two of them of the beta-Proteobacteria and a third one of the gamma-Proteobacteria displaying 75% and 35% homology in their deduced amino acid sequences, respectively. This gene has proven to be a suitable molecular marker to study AOB, as well as providing a new insight into the classification of this group.
Amino Acid Sequence↗
Phylogenetic utility of protein (RPB2, beta-tubulin) and ribosomal (LSU, SSU) gene sequences in the systematics of Sordariomycetes (Ascomycota, Fungi).
The Sordariomycetes is an important group of fungi whose taxonomic relationships and classification is obscure. There is presently no multi-gene molecular phylogeny that addresses evolutionary relationships among different classes and orders. In this study, phylogenetic analyses with a broad taxon sampling of the Sordariomycetes were conducted to evaluate the utility of four gene regions (LSU rDNA, SSU rDNA, beta-tubulin and RPB2) for inferring evolutionary relationships at different taxonomic ranks. Single and multi-gene genealogies inferred from Bayesian and Maximum Parsimony analyses were compared in individual and combined datasets. At the subclass level, SSU rDNA phylogenies demonstrate their utility as a marker to infer phylogenetic relationships at higher levels. All analyses with SSU rDNA alone, combined LSU rDNA and SSU rDNA, and the combined 28 S rDNA, SSU rDNA and RPB2 datasets resulted in three subclasses: Hypocreomycetidae, Sordariomycetidae and Xylariomycetidae, which correspond well to established morphological classification schemes. At the ordinal level, the best resolved phylogeny was obtained from the combined LSU rDNA and SSU rDNA datasets. Individually, the RPB2 gene dataset resulted in significantly higher number of parsimony informative characters. Our results supported the recent separation of Boliniaceae, Chaetosphaeriaceae and Coniochaetaceae from Sordariales and placement of Coronophorales in Hypocreomycetidae. Microascales was found to be paraphyletic and Ceratocystis is phylogenetically associated to Faurelina, while Microascus and Petriella formed another clade and basal to other members of Halosphaeriales. In addition, the order Lulworthiales does not appear to fit in any of the three subclasses. Congruence between morphological and molecular classification schemes is discussed.
Ascomycota↗
Non-Hodgkin's lymphoma.
Lymphoid neoplasia is a complex area comprising multiple diseases with varied pathology, treatment, and outcome. The non-Hodgkin's lymphomas are reviewed here. Non-Hodgkin's lymphomas, collectively, represent the sixth most common cancer in the United States as well as the sixth most common cause of cancer deaths. The overall incidence of non-Hodgkin's lymphoma has risen steadily over the past four decades. Although some of this is attributable to human immunodeficiency virus (HIV)-associated lymphoma, HIV-associated disease accounts for only a small part of the increase in lymphoma. As our knowledge of normal as well as neoplastic lymphoid development has expanded on the basis of histopathology as well as adjunct cellular and molecular techniques, multiple classifications have been proposed to take these into account. The clinical relevance to our understanding of non-Hodgkin's lymphoma is the concept that various lymphoid cancers are counterparts of stages of normal lymphoid development. Stages of lymphoid development in terms of cell surface markers and immunoglobulin gene rearrangements have been well characterized. These are particularly applicable to the early B-cell development, which is antigen-independent and occurs in the bone marrow. Diseases correlating with these stages are largely acute lymphocytic and lymphoblastic leukemia/lymphoma and high-grade lymphomas, such as Burkitt's lymphomas. Much has been learned recently about subsequent antigen-dependent B-cell development in secondary lymphoid organs to improve our understanding of the corresponding stages of B-cell neoplasia. Many of these stages correlate with more recently described entities such as mantle cell and marginal zone lymphomas. Histologic study remains crucial in determining the subtype of NHLs, whereas immunohistochemistry, surface phenotype, and molecular studies are useful in selected cases. Although some lymphoma classifications may be better in terms of understanding the lymphoma biology, the working formulation remains useful to guide clinical decision making. Lymphomas classified as low grade are considered incurable with standard therapy when diagnosed, as is usual, at advanced stages. Different subtypes may have different median survivals, but the goal has typically been palliation, whereas experimental approaches are clearly needed. Intermediate and high-grade lymphomas are potentially curable with aggressive combination chemotherapy. Recent evidence suggests that CHOP chemotherapy is as effective as more complex regimens. Still, 40% to 50% of patients are cured. Prognostic factor analysis has allowed separation of subgroups with much better survival in whom CHOP is adequate versus those with much poorer survival in whom experimental approaches are rational. Additional subtypes of lymphomas have been described and characterized since the working formulation was developed, including mucosa-associated lymphoid tissue tumors (MALT-oma), mantle zone lymphoma, anaplastic large cell lymphoma and AILD-like T-cell lymphoma. Approaches to these entities are still being optimized. Newer approaches, including high-dose therapy with stem cell support, biologic agents, and newer chemotherapeutic agents are discussed, as are special situations such as localized lymphoma of certain sites and lymphoma in immunosuppressed patients.
Antineoplastic Agents↗
Graying anatomy? Toward molecular tumor characterization.
Will anatomical tumor classification become history as we make way for molecular characterization in oncology? Howard McLeod, Fred Eshelman Distinguished Professor of Pharmacy and Professor of Medicine at the University of North Carolina (NC, USA), is internationally recognized for his work on the pharmacogenomic analysis of cancer treatments. Here, he offers Pharmacogenomics his perspectives on the prospects for practical implementation of PGx in clinical care and the corresponding timescales. He and colleagues have already identified specific genetic components of several drugs that have lead to the US FDA changing the drug package inserts to identify patient groups that are genetically predisposed to risk of severe side effects or inadequate benefit. He is currently working with the large national clinical trials groups--such as Cancer and Leukemia Group B--to confirm that findings from small institutional studies will actually translate into better therapy across the USA.
Humans↗
Cytogenetics of myelodysplastic syndromes.
This review focuses on karyotypic and molecular findings of myelodysplastic syndromes (MDS). Genetic entities are distinct on the basis of structural (deletions, translocations, inversions) or numerical chromosomal abnormalities (trisomies, monosomies). New information about the amount and nature of malignant cells in MDS, as well as of genes rearranging in specific translocations, recently provided by molecular cytogenetics, are analysed. Integration of clinical-haematological classifications with cytogenetic and molecular findings is discussed
Adult↗