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PubMed2002

Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding.

In tick salivary glands, genes induced during blood feeding result in the expression of new proteins secreted into tick saliva. These proteins are potentially involved in modulation of vertebrate host immune and hemostatic responses. In this study, subtractive and full-length cDNA libraries were constructed by use of mRNA extracted from salivary glands of unfed and 5-day engorged Ixodes ricinus. Sequences from these 2 libraries were compared with European Molecular Biology Laboratory (EMBL)/GenBank databases, which led to their classification into 2 major groups. The first group comprises cDNAs that failed to match or showed low homology to genes of known function. The second group includes sequences that showed high homology to genes of known function--for example, anticoagulants, inhibitors of platelet aggregation, and immunomodulatory proteins. Analyses of corresponding proteins suggest that they may be secreted by salivary gland cells. To study the properties of the recombinant proteins, selected cDNAs were expressed in mammalian or bacterial systems.

Amino Acid Sequence↗
PubMed2003

Molecular etiology of mature T-cell non-Hodgkin's lymphomas.

T-cell non-Hodgkin's lymphomas (NHL) represent approximately 10-15% of all lymphomas diagnosed in Western countries. Significant progress has been made over the last 2 decades in defining non-random chromosomal abnormalities. Cytogenetic and molecular analyses have enhanced diagnostic capabilities as well as improved classification and prognostication for T-cell NHL. Gamma-delta T-cell receptor (TCR) clonality now represents the more common TCR rearrangement in subcutaneous panniculitis-like T-cell lymphoma (SCPTCL), hepatosplenic T-cell lymphoma (HSTCL), extranodal NK/T-cell lymphoma, nasal type and enteropathy-type intestinal T-cell lymphoma (EITCL). Non-random, recurrent chromosome abnormalities such as isochrome 7 with HSTCL, complex karyotypes with peripheral T-cell lymphoma, not otherwise characterized (PTCL-NOC), trisomies 3 and 5 with angioimmunoblastic lymphoma (AIL) and t(2;5) with systemic anaplastic T-cell lymphoma have been recognized. Furthermore, identification of relevant protooncogenes and tumor suppressor genes involved in the pathogenesis of T-cell NHL such as the NPM/ALK fusion protein, p53, cyclin dependent kinase inhibitors (p15, p16, p21) and EBV as well as their interplay with the various regulatory pathways of cell cycle progression and apoptosis represent potential candidates for molecular-based therapy. This review presents a detailed analysis of the molecular and genetic perturbations present in mature T-cell lymphomas including discussion of how tumor-specific alterations impact on clinical outcome. Future studies in T-cell NHL are likely to provide additional disease-specific chromosomal translocations and molecular alterations with important translational implications.

Humans↗
PubMed2002

Applications of artificial neural network in AIDS research and therapy.

In recent years considerable effort has been devoted to applying pattern recognition techniques to the complex task of data analysis in drug research. Artificial neural networks (ANN) methodology is a modeling method with great ability to adapt to a new situation, or control an unknown system, using data acquired in previous experiments. In this paper, a brief history of ANN and the basic concepts behind the computing, the mathematical and algorithmic formulation of each of the techniques, and their developmental background is presented. Based on the abilities of ANNs in pattern recognition and estimation of system outputs from the known inputs, the neural network can be considered as a tool for molecular data analysis and interpretation. Analysis by neural networks improves the classification accuracy, data quantification and reduces the number of analogues necessary for correct classification of biologically active compounds. Conformational analysis and quantifying the components in mixtures using NMR spectra, aqueous solubility prediction and structure-activity correlation are among the reported applications of ANN as a new modeling method. Ranging from drug design and discovery to structure and dosage form design, the potential pharmaceutical applications of the ANN methodology are significant. In the areas of clinical monitoring, utilization of molecular simulation and design of bioactive structures, ANN would make the study of the status of the health and disease possible and brings their predicted chemotherapeutic response closer to reality.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Sample preparation and in situ hybridization techniques for automated molecular cytogenetic analysis of white blood cells.

With the advent of in situ hybridization techniques for the analysis of chromosome copy number or structure in interphase cells, the diagnostic and prognostic potential of cytogenetics has been augmented considerably. In theory, the strategies for detection of cytogenetically aberrant cells by in situ hybridization are simple and straightforward. In practice, however, they are fallible, because false classification of hybridization spot number or patterns occurs. When a decision has to be made on molecular cytogenetic normalcy or abnormalcy of a cell sample, the problem of false classification becomes particularly prominent if the fraction of aberrant cells is relatively small. In such mosaic situations, often > 200 cells have to be evaluated to reach a statistical sound figure. The manual enumeration of in situ hybridization spots in many cells in many patient samples is tedious. Assistance in the evaluation process by automation of microscope functions and image analysis techniques is, therefore, strongly indicated. Next to research and development of microscope hardware, camera technology, and image analysis, the optimization of the specimen for the (semi)automated microscopic analysis is essential, since factors such as cell density, thickness, and overlap have dramatic influences on the speed and complexity of the analysis process. Here we describe experiments that have led to a protocol for blood cell specimen that results in microscope preparations that are well suited for automated molecular cytogenetic analysis.

Acetic Acid↗
PubMed1998

Classifications of the International League Against Epilepsy: time for reappraisal.

Recent advances in neurodiagnostic technology, new insights into fundamental neuronal mechanisms of epilepsy, and rapid developments in molecular genetics have greatly improved our understanding of epileptic seizures and epileptic disorders since 1981, when the current International Classification of Epileptic Seizures was adopted, and since 1989, when the International Classification of Epilepsies, Epileptic Syndromes, and Related Disorders was adopted. Although both have been universally accepted and have proven to be of considerable clinical value, it has become clear that more is needed for specific applications of growing importance, such as presurgical evaluation, clinical pharmacology trials, and epidemiological studies. Therefore, an International League Against Epilepsy (ILAE) task force has evaluated the need for revising our current classification and terminology and has begun developing four specific documents. The first is a descriptive terminology for ictal phenomena, incorporating some of the concepts included in the preceding paper by Dr. Hans Lüders; however, this will be a glossary, not a classification. The second is a classification of epileptic seizures based on known or presumed pathophysiological and anatomic substrates, to replace the current classification, which is based entirely on phenomenology. The third is a classification of epileptic syndromes and epileptic diseases, adapted from the current Classification of Epilepsies, Epileptic Syndromes, and Related Disorders, which will take into account the fact that disorders with unique etiologies, such as a single gene, should be considered diseases, and which will be reorganized for maximum practical application to differential diagnosis. The fourth is a new classification of functional disability due to seizures or epilepsy, based on a new impairment classification for neurological disorders being developed by the World Health Organization. Working groups are currently in the process of developing each of these documents, and their chairs would benefit from any comments or suggestions from those who ultimately will be using these systems of classification and terminology.

Epilepsy↗
PubMed1994

Simultaneous immunoglobulin/T-cell receptor gene rearrangements and multiclonality in childhood acute lymphoblastic leukemia.

Twenty-five children less than 16 years of age with acute lymphoblastic leukemia (ALL) were investigated with immunologic, cytogenetic and molecular genetic techniques at diagnosis. All pre-B-cell ALL showed clonal rearrangements in the immunoglobulin heavy chain gene (JH and/or C mu). A very high proportion of the pre-B-cell leukemias (17 of 23 cases) also showed clonal rearrangements in T-cell receptor genes (T gamma and/or T beta). The two T-cell leukemias exhibited clonal T-cell receptor gene rearrangements and in one JH and kappa light chain rearrangements also. The T-cell receptor gene rearrangements found in pre-B-cell leukemias appeared to occur randomly with respect to the T beta and T gamma genes. A significant proportion of the leukemias (at least 24%) seemed to harbor more than one malignant (sub)clone at diagnosis. Cytogenetic studies revealed a clonal abnormality in 10 cases. Only 2 showed hyperdiploidy (> 50 chromosomes). The only correlation between cytogenetic findings and rearrangement patterns was extra bands corresponding to a possible trisomy of chromosome 14. Our data indicate, in line with previous studies, that childhood ALL has complex rearrangement patterns not useful for lineage sub-classification. For this purpose immunophenotyping appears to be superior. However, molecular analysis can reveal the presence of more than one clone not detected by immunophenotyping or karyotyping, and distribution of clones in different compartments. In this study no correlation with clinical outcome was observed.

Adolescent↗
PubMed1985

[Classification and principles of the use of vasodilators in the treatment of left ventricular insufficiency].

Vasodilators have been widely used in recent years for the treatment of severe left ventricular failure (LVF). However, amongst these drugs, not all have the same therapeutic effects, but they differ from one another in molecular structures, cellular mechanisms, haemodynamic actions and modes of administration. A three tier classification is proposed with the single objective of facilitating the therapeutic choice: mechanism of action: this property distinguishes the alpha-blockers from the beta-2 sympathomimetics, calcium antagonists, angiotensin converting enzyme inhibitors and prostacyclin biosynthesis inducers. Some molecules such as hydralazine, whose mechanism of action remains unclear, cannot be classified in this way; haemodynamic effects: these effects can be used to distinguish vasodilators which act mainly on the venous sector from arterial and mixed vasodilators. The knowledge of the preferential site ol action of these molecules helps to adapt the choice of treatment to the initial haemodynamic profile of each patient; pharmacokinetics: these properties distinguish molecules active only by intravenous administration, better adapted for the treatment of acute LVF in the intensive care unit, from those active orally which can be used for long-term ambulatory therapy of chronic cardiac failure. Trinitrin and its derivatives occupy an intermediate position because of their relatively low bioavailability after oral administration: long-term administration is not always easy and may require special modes of administration (i.e. percutaneous). Vasodilators have been widely used in cardiac failure for about 5 years; the results of some medium term controlled therapeutic trials are now available and confirm the efficacy of these drugs but also define their limitations: variable therapeutic efficacy: the number of responders ranges from 30 to 60 p. 100 according to the molecule used.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Channel Blockers↗
PubMed2005

A multidimensional approach for detecting species patterns in Malagasy vertebrates.

The biodiversity of Madagascar is extraordinarily distinctive, diverse, and endangered. It is therefore urgent that steps be taken to document, describe, interpret, and protect this exceptional biota. As a collaborative group of field and laboratory biologists, we employ a suite of methodological and analytical tools to investigate the vertebrate portion of Madagascar's fauna. Given that species are the fundamental unit of evolution, where micro- and macroevolutionary forces converge to generate biological diversity, a thorough understanding of species distribution and abundance is critical for understanding the evolutionary, ecological, and biogeographic forces that have shaped Malagasy vertebrate diversity. We illustrate the means by which we apply Mayr's "three basic tasks" of the systematist [Mayr, E. (1942) Systematics and the Origin of Species from the Viewpoint of a Zoologist (Harvard Univ. Press, Cambridge, MA)] to identify, classify, and study the organisms that together constitute Madagascar's vertebrate community. Using field inventory methods, specimen-based studies, and morphological and molecular analyses, we formulate hypotheses of species identity that then serve as the foundation for subsequent studies of biology and history. Our experience, as well as that of other investigators, has shown that much of the vertebrate species diversity in Madagascar is "cryptic" for both biological and practical reasons. Beyond issues of cryptic biological diversity, the resolution of species identity in Madagascar has been hampered because of a lack of vouchered comparative material at the population level. Through our activities, we are attempting to remedy these limitations while simultaneously enhancing research capacity in Madagascar.

Animals↗
PubMed1996

[Histologic grading of chondrosarcoma. A qualitative and quantitative analysis of 74 cases of the Hamburg bone tumor register].

Chondrosarcomas are frequent malignant bone tumors. Aside from different subtypes, such as dedifferentiated, mesenchymal and clear-cell chondrosarcoma, chondrosarcomas (classical chondrosarcoma) show different grades of differentiation. The borderline between chondroma and classical chondrosarcoma is not clearly defined. The same chondrosarcoma can be graded differently at different institutes. Standardized therapy concepts are currently in preparation. As the Hamburg Bone Tumor Registry is often consulted for chondrogenic tumors, the histological criteria are based on a series of 74 chondrosarcomas recorded there. The emphasis has been laid on a classification which can be used in daily routine and which is reproducible and in agreement with the classifications of other international groups. Grade I chondrosarcomas (50%) can be distinguished only by growth criteria. The nuclei are small and show high chromatin density. Grade II chondrosarcomas (42%) have medium-sized, regular nuclei with loose chromatin structure. The chondrocytes of grade III cases (8%) show polymorphic nuclei. Binucleas forms, the number of mitoses and cellularity all show considerable overlap for all three grades. So far there are no immunohistological and molecular biological methods for reliable differentiation. The therapeutic consequences of the classification into grades are thorough curettage, in the case of grade I tumors, or complete resection, for grade II and III cases. The long-term results, however, need to be confirmed by a larger number of cases. From 1991 to 1995 the method was applied and proved to be easily practicable in daily diagnostic routine. Some 104 cases of classical chondrosarcomas (grade I 53%, grade II 39%, grade III 8%) were analyzed. Two pathologists both assigned the same grade in 90% of cases.

Adult↗
PubMed1999

International Union Against Cancer. Classification of isolated tumor cells and micrometastasis.

BACKGROUND: Findings of isolated (disseminated or circulating) tumor cells (ITC) by immunocytochemistry and molecular pathology methods have led to varied interpretations and different applications of the TNM system. METHODS: An analysis of the relevant literature was undertaken. In addition, optional proposals for the classification of ITC, micrometastasis, and cytologic results in pleural and peritoneal washings are presented. RESULTS: Immunocytochemistry has a lower false-positive rate than nonmorphologic methods such as flow cytometry or the polymerase chain reaction; therefore the method(s) used always should be recorded. At the current time, the independent prognostic significance of ITC in regional lymph nodes and in the general circulation (blood, bone marrow, and other distant sites) is difficult to assess. To enable comparisons of treatment results and to avoid variation in staging, a finding of ITC should not be considered in the TNM and residual tumor (R) classifications, at least not at the current time. However, for future evaluation of their prognostic significance, the respective findings should be documented according to uniform criteria. CONCLUSIONS: ITC should be distinguished from micrometastasis. To investigate the independent prognostic significance of ITC and of positive lavage cytology, uniform data collection according to the proposed coding schema is recommended.

Ascitic Fluid↗
PubMed2026

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Lowry-Wood syndrome↗
PubMed1994

Molecular pharmacology of serotonin receptors.

The serotonin system has long been thought to play a role at several steps in the cycle of alcohol abuse. Initial motivation may be triggered by anxiety, which may exhibit a serotonergic component (5-HT1A receptor). Alcohol can potentiate the opening of 5-HT3 receptor ion channels, and agents which elevate serotonergic tone, including serotonergic agonists, uptake inhibitors and releasers, have shown promise in assisting with recovery from alcoholism. In this review, recent advances in serotonin receptor research are presented, with a special emphasis on the impact and interpretation of molecular biological data. Genetic and pharmacological concepts of receptor subtypes are reviewed and related to a new classification system for the 14 currently recognized subtypes of serotonin receptors. The current and likely future impact on drug design of the molecular approach to serotonin receptors is discussed. Finally, the question of why there are so many serotonin receptor subtypes is examined, along with possible roles of multiple G protein and second messenger pathways, and their effect on conserved domains of these receptor proteins.

Alcoholism↗
PubMed2004

Phenotypic and genetic diversity of Lactococcus lactis and Enterococcus spp. strains isolated from Northern Spain starter-free farmhouse cheeses.

To evaluate a previous phenotypic classification of lactococci, 39 presumed lactococcal strains were classified by molecular techniques. The strains were also subjected to several typing techniques to estimate the phenotypic and genetic diversity present in original populations from starter-free farmhouse cheeses. Partial Amplified rDNA Restriction Analysis (partial ARDRA) with either restriction enzyme MboII or HhaI divided these isolates into four distinctive groups. Sequencing of representative amplicons identified 29 isolates as belonging to Lactococcus lactis subsp. lactis (24) and Lactococcus lactis subsp. cremoris (5). The remaining 10 isolates were shown to be Enterococcus durans (8) and Enterococcus faecalis (2), which were misclassified by the traditional tests. Thus, partial ARDRA was successfully used to classify wild Lactococcus-like strains into Lactococcus and Enterococcus species. The technique also allowed differentiation of L. lactis strains at subspecies level. The 29 strains of L. lactis showed five different fermentation profiles, four distinct Random Amplification of Polymorphic DNA (RAPD) profiles, and 14 unrelated profiles by both Restriction Fragment Length Polymorphism analyzed by Pulsed Field Gel Electrophoresis (RFLP-PFGE) and Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS-PAGE). Using the same techniques, the 10 enterococcal strains showed four fermentation profiles, four RADP, and six by RFLP-PFGE and SDS-PAGE, respectively. Several typing techniques, especially RFLP-PFGE and SDS-PAGE, revealed wide phenotypic and genetic variability in both the lactococcal and enterococcal isolates. Two simple, rapid and cheap techniques (partial ARDRA and SDS-PAGE) are proposed as reliable tools for the classification and typing of new lactococcal-like isolates.

Bacterial Typing Techniques↗
PubMed2001

Mesorhizobium chacoense sp. nov., a novel species that nodulates Prosopis alba in the Chaco Arido region (Argentina).

Low-molecular-weight RNA analysis was performed for the identification and classification of 20 Argentinian strains isolated from the root nodules of Prosopis alba. SDS-PAGE of total cellular proteins, determination of the DNA base composition, DNA-DNA reassociation experiments and physiological and biochemical tests were also carried out for these strains and the whole 16S rRNA gene was sequenced from one of the strains, strain LMG 19008T. Results of the genotypic and phenotypic characterization showed that the strains isolated in this study belong to a group that clustered in the genus Mesorhizobium. The results of DNA-DNA hybridizations showed that this group is a novel species of this genus. The name Mesorhizobium chacoense sp. nov. is proposed for this species. The type strain is LMG 19008T (= CECT 5336T).

Anti-Bacterial Agents↗
PubMed2004

Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia.

Several molecular and histopathological prognostic markers have been proposed for the therapeutic stratification of medulloblastoma patients. Amplification of the c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been associated with worse clinical outcomes. In contrast, high TrkC mRNA expression generally presages longer survival. The goal of this study was to evaluate the prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and compare them to histopathological classification. We used in situ hybridization to measure expression of these molecular markers. c-myc mRNA was detected in 18 of 59 (31%) cases, and was significantly associated with shorter patient survival times on both univariate and multivariate analyses (p = 0.04). The presence of c-myc mRNA was also significantly associated with tumor anaplasia. While survival rates were higher for patients with low N-myc or high TrkC expression, these differences were not statistically significant. The group of patients with either moderate or severely anaplastic tumors showed only a trend towards shorter survival (p = 0.11). However, severe anaplasia alone was significantly prognostic (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1 mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway activation, was more common in medulloblastomas with high c-myc than in tumors overall, but the difference was not statistically significant. No Mxi-1 mutations were detected in the 22 cases examined. The association we describe between c-myc expression, tumor anaplasia, and worse clinical outcomes provides further evidence for the importance of this oncogene in medulloblastoma pathobiology.

Active Transport, Cell Nucleus↗
PubMed2004

PCR-SSCP as a molecular tool for the identification of Benedeniinae (Monogenea: Capsalidae) from marine fish.

PCR-based single strand conformation polymorphism (SSCP) analysis was used to characterize monogenean specimens of the subfamily Benedeniinae of morphologically uncertain specific status from different marine fish species, using Neobenedenia melleni, N. girellae and Entobdella corona for comparison. The first internal transcribed spacer (ITS-1) and the 5' terminal variable region (D1-D3 domains) of the large subunit ribosomal DNA (lsrDNA) were amplified separately from individual monogeneans, and the amplicons were subjected to PCR-SSCP analyses, followed by direct sequencing. Both SSCP patterns and the ITS-1 sequences data allowed specimens representing Entobdella spp. from the host Taeniura melanospilos to be unequivocally distinguished from those representing Neobenedenia spp. and those representing Benedenia spp. Neobenedenia girellae, a morphologically controversial species, had identical SSCP banding pattern and ITS-1 sequence to that of N. melleni, supporting the proposal that N. girellae is a synonym of N. melleni. Neobenedenia spp. and Benedenia spp. had identical SSCP patterns and ITS-1 sequences. These findings and the PCR-SSCP approach taken should have implications for the accurate identification and assessment of taxonomic validity of other important monogenean groups of the marine fish.

Animals↗