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PubMed1995

[Value of molecular biology methods for diagnosis in bacteriology].

Progress in molecular biology has led to the development of new tools for bacteriological diagnosis. Sporadic genes coding for virulence factors can be detected with highly specific genetic probes applied to cultured bacteria. Such genetic probes can also be used to specifically identified cultured bacteria whose general taxonomic classification is known. Another advantage of molecular genetics is the possibility that the cell culture step may not be needed, bacteria being identified directly in the sample specimen. Such techniques are particularly interesting to identify bacteria which are difficult to culture (for example: Borrelia burgdorferi, Chlamydia trachomatis) or which grow slowly (mycobacteria). The bacterial DNA must be isolated and amplified with an enzyme reaction. This is a critical step in the method: several positive and negative controls are required. When performed under optimal conditions, amplification techniques are excellent methods which can offer results similar to culture methods in culturable bacteria. Finally, molecular biology can be used to identify previously cultured bacteria for which there is no taxonomic orientation. Here the ribosome 165 DNA must be amplified and sequenced. The sequence is then compared with a data bank allowing classification. One could image future techniques applied to certain pathology samples for the detection and identification of bacteria without need for a culture step. However, direct microscope examination and bacterial culture remain the basic methods for bacteriologic diagnosis, the advantages and disadvantages of molecular biology leading to its use a complementary method for improving the quality of the diagnosis.

Bacteriological Techniques↗
PubMed1992

Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma.

The molecular genetic alterations in colorectal carcinoma are among the best understood of any common human cancer. Identified abnormalities include both dominant-acting oncogenes (ras, myc, src) and suppressor genes which undergo inactivation or deletion (deleted in colorectal carcinoma gene [DCC], p53, adenomatous polyposis coli gene [APC], and probably loci on chromosomes 1p and 22q). Accumulation of multiple abnormalities is evident in the adenoma-carcinoma sequence with a preferential order, and alteration of DNA methylation is an especially early event. Identification of molecular genetic markers useful for classification and staging of colorectal carcinoma is in its infancy. Deletion of the p53 gene on chromosome 17p, deletion of the DCC gene on 18q, and high fractional allelic loss (fraction of evaluable nonacrocentric autosomal arms with deletion) have been associated with distant metastases and with poorer prognosis in patients without initial evidence of disseminated disease. Additional studies are needed to determine the possible role of these alterations in clinical management.

Chromosome Deletion↗
PubMed2004

Molecular genetics of the ichthyoses.

The ichthyoses are a large, clinically, genetically, and etiologically heterogeneous group of disorders of cornification due to abnormal differentiation and desquamation of the epidermis. Although they differ in clinical features, inheritance, and structural and biochemical abnormalities of the epidermis, they often pose a diagnostic challenge. For each of the 12 ichthyoses and related disorders described here, the major disease genes have been identified and genotype-phenotype correlation have begun to emerge. The molecular findings reveal the functional importance and interactions of many different epidermal proteins and metabolic pathways, including major structural proteins (keratins, loricrin), enzymes involved in lipid metabolism (transglutaminase 1, lipoxygenases, fatty aldehyde dehydrogenase, steroid sulfatase, glucocerebrosidase, Delta8-Delta7 sterol isomerase, 3beta-hydroxysteroid dehydrogenase), and protein catabolism (LEKTI), peroxisomal transport and processing (Peroxin 7 receptor, Phytanoyl-CoA hydroxylase) and DNA repair (proteins of the transcription repair complex). This review highlights the spectacular advances in the molecular genetics and biology of heritable ichthyoses over the past decade. It illustrates the power of molecular diagnostics for refining disease classification, providing prenatal diagnosis, improving genetic counseling, and clinical management.

DNA Repair↗
PubMed1996

Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

Adult↗
PubMed2006

Class distinction between follicular adenomas and follicular carcinomas of the thyroid gland on the basis of their signature expression.

BACKGROUND: Nodules of the thyroid gland are observed frequently in patients who undergo ultrasound studies. The majority of these nodules are benign, corresponding to goiters or adenomas, and only a small fraction corresponds to carcinomas. Among thyroid tumors, the diagnosis of follicular adenocarcinomas by preoperative fine-needle aspiration biopsy is a major challenge, because it requires inspection of the entire capsule to differentiate it from adenoma. Consequently, large numbers of patients undergo unnecessary thyroidectomy. METHODS: Using data from gene expression analysis, the authors applied Fisher linear discriminant analysis and searched for expression signatures of individual samples of adenomas and follicular carcinomas that could be used as molecular classifiers for the precise classification of malignant and nonmalignant lesions. RESULTS: Fourteen trios of genes were described that fulfilled the criteria for the correct classification of 100% of samples. The robustness of these trios was verified by using leave-1-out cross-validation and bootstrap analyses. The results demonstrated that, by combining trios, better classifiers could be generated that correctly classified >92% of samples. CONCLUSIONS: The strategy of classifiers based on individual signatures was a useful strategy for distinguishing between samples with very similar expression profiles.

Adenocarcinoma, Follicular↗
PubMed2001

The new World Health Organization classification of lymphomas: the past, the present and the future.

The REAL Classification of lymphomas, proposed in 1994, represents a new paradigm in lymphoma classification, consisting of a list of biologic entities defined by clinicopathologic and immunogenetic features. The non-Hodgkin's lymphomas comprise precursor lymphoblastic and mature cell neoplasms of B, T or putative natural killer cell lineage. An individual entity can exhibit a range of morphologic appearances and a range of clinical behavior. The categories in Hodgkin's lymphomas are identical to the widely used Rye classification except for the additional of a new category termed 'lymphocyte-rich classical Hodgkin's lymphoma'. The REAL classification has been validated by a major multi-institutional study involving 1378 cases (The Non-Hodgkin's Lymphoma Classification Project), showing that it is both reproducible and clinically relevant. The new World Health Organization classification of hematopoietic and lymphoid tumors, to be published in 2001, is a joint project of the Society for Hematopathology and European Association of Hematopathologists, under the auspices of the World Health Organization. This classification includes not only lymphoid neoplasms, but also myeloid, histiocytic and mast cell neoplasms. The lymphoma component of the classification is merely an update of the REAL classification, with minor changes necessitated by new information that has become available since its proposal. A conceptual grouping of the non-Hodgkin's lymphomas into four categories (indolent, aggressive, highly aggressive, and localized indolent) is also presented in this review. The next major impetus influencing the approach to lymphoma classification will no doubt be molecular genetics, in particular DNA microarrays, which will yield an enormous amount of new data that will aid in the understanding of lymphomas.

Forecasting↗
PubMed2004

Limb sparing surgery for pediatric musculoskeletal tumors.

There has been an unprecedented improvement in the survival outcome of children with extremity sarcoma as well as a corresponding increase in percentage of limb-sparing surgeries being performed over the past many decades. This has been, in part, due to the improved imaging modalities, newer surgical techniques, and advences in neoadjuvant chemotherapy. Limb-sparing surgery for primary bone and soft-tissue malignancies in children is becoming an acceptable option of surgical treatment in most cases today. This article outlines the demographics, classification, clinical presentation, imaging, and molecular genetics of pediatric mosculoskeletal tumors and discusses the current treatment principles with emphasis on the state-of-the-art surgical management and limb-sparing techniques for children with extremity sarcoma.

Amputation, Surgical↗
PubMed2005

Identification of fatty acid binding proteins as markers associated with the initiation and/or progression of renal cell carcinoma.

Renal cell carcinoma (RCC) representing the most common neoplasia of the kidney in Western countries is a histologic diverse disease with an often unpredictable course. The prognosis of RCC is worsened with the onset of metastasis, and the therapies currently available are of limited success for the treatment of metastatic RCC. Although gene expression analyses and other methods are promising tools clarifying and standardizing the pathological classification of RCC, novel innovative molecular markers for the diagnosis, prognosis, and for the monitoring of this disease during therapy as well as potential therapeutic targets are urgently needed. Using proteome-based strategies, a number of RCC-associated markers either over-expressed or down-regulated in tumor lesions in comparison to the normal epithelium have been identified which have been implicated in tumorigenesis, but never linked to the initiation and/or progression of RCC. These include members of the fatty acid binding protein family, which have the potential to serve as diagnostic or prognostic markers for the screening of RCC patients.

Biomarkers, Tumor↗
PubMed2003

[Congenital malformations of the cerebral brain. 1: Malformations of the cerebral cortex].

Disorders of supratentorial cortical development are usually divided into disorders of neuronal proliferation, neuronal migration and cortical organization. Based upon molecular biologic discoveries, a modified classification has recently been proposed. The category of malformations of abnormal neuronal and glial proliferation and apoptosis now includes microlissencephalies, megalencephalies, hemimegalencephalies and cortical dysplasias with balloon cells. Malformations due to abnormal neuronal migration now subsume the lissencephaly spectrum including the subcortical band heterotopias, the cobblestone complex and the group of heterotopias. Malformations due to abnormal cortical organization include the spectrum of polymicrogyria and schizencephaly as well as cortical dysplasias without balloon cells. High-resolution magnetic resonance imaging (MRI) has led to an increasing awareness of these malformations. This article aims to illustrate the classification, MRI presentation and relevant clinical features of the most commonly encountered disorders of cortical development.

Brain↗
PubMed2002

Functional constraints of the Cu,Zn superoxide dismutase in species of the Drosophila melanogaster subgroup and phylogenetic analysis.

The phylogenetic relationships among the Drosophila melanogaster subgroup species were analyzed using approximately 1550-nucleotide-long sequences of the Cu,Zn SOD gene. Phylogenetic analysis was performed using separately the whole region and the intron sequences of the gene. The resulting phylogenetic trees reveal virtually the same topology, separating the species into distinct clusters. The inferred topology generally agrees with previously proposed classifications based on morphological and molecular data. The amino acid sequences of the Cu,Zn SOD of the D. melanogaster subgroup species reveal a high-conservation pattern. Only 3.9% of the total amino acid sites are variable, and none affects the major structural elements. Comparison of the Drosophila Cu,Zn SOD amino acid sequences with the Cu,Zn SOD of Bos taurus and Xenopus laevis (whose three-dimensional structure has been elucidated) reveals conservation of all the protein's functionally important amino acids and no substitutions that dramatically change the charge or the polarity of the amino acids.

Amino Acid Sequence↗
PubMed2004

The chemical hunt for the identification of drugable targets.

Chemical biology has emerged as a new scientific discipline to change the way scientists approach and study the interface between chemistry, biology, and physics. By integrating the knowledge base of the human genome with the power of diverse and flexible chemical technology platforms, the ultimate goal is to define the 'rules of engagement' for small molecules and their use in basic biology and in drug discovery. Herein, we highlight the current counterpoles of the chemical biology philosophy in the framework between conformational diversity and informational complexity. Expanding the growing molecular recognition information matrix into classification of diseases and immediate mechanistic in-vivo proof of concept models represent the next development phase in a field that, unlike any other due to its multidisciplinary nature, unifies basic scientists and drug discoverers.

Animals↗
PubMed2005

Revealing the genomic heterogeneity of melanoma.

The melanoma genome possesses numerous recurrent chromosomal rearrangements, and embedded within this complexity are clues critical to disease pathogenesis and response to therapy. High-resolution genome-wide DNA copy number approaches, in conjunction with gene-specific mutational analyses, appear poised to define keystone molecular events, provide more accurate classification schemes, and set the stage for the design of rational therapies that may finally have an impact on survival of this deadly disease.

Alternative Splicing↗
PubMed2006

High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients.

To identify genetic events underlying the genesis and progression of multiple myeloma (MM), we conducted a high-resolution analysis of recurrent copy number alterations (CNAs) and expression profiles in a collection of MM cell lines and outcome-annotated clinical specimens. Attesting to the molecular heterogeneity of MM, unsupervised classification using nonnegative matrix factorization (NMF) designed for array comparative genomic hybridization (aCGH) analysis uncovered distinct genomic subtypes. Additionally, we defined 87 discrete minimal common regions (MCRs) within recurrent and highly focal CNAs. Further integration with expression data generated a refined list of MM gene candidates residing within these MCRs, thereby providing a genomic framework for dissection of disease pathogenesis, improved clinical management, and initiation of targeted drug discovery for specific MM patients.

Chromosomes, Human↗
PubMed2004

Multivariate adaptive regression splines (MARS) in chromatographic quantitative structure-retention relationship studies.

The multivariate adaptive regression splines (MARS) methodology was applied to build quantitative structure-retention relationships (QSRRs). The response (dependent variable) in the MARS models consisted of the logarithms of the extrapolated retention factors (log k(w)) of 83 structurally diverse drugs on a Unisphere PBD column, using isocratic elutions at pH 11.7. A set of 266 molecular descriptors was used as predictor (independent) variables in the MARS model building. The optimal MARS model uses 34 basis functions to describe the retention and has acceptable predictive properties for new objects. The molecular descriptors included in the model describe hydrophobicity, molecular size, complexity, shape and polarisability. Some additional MARS models were created using alternative strategies. These include models with log P as the single predictor and models obtained with only the three most important molecular descriptors. The use of classification and regression trees (CART) as feature selection technique for predictor variables used in the MARS model was also investigated. Further, it is also studied whether allowing quadratic terms instead of interaction terms might lead to better MARS models.

Chromatography, Liquid↗
PubMed2025

Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia.

PURPOSE: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated. METHODS: 164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA. RESULTS: Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance ("depth") between the interruptions (mostly nontriplet) and the 3' end of the expansion (P < .001), the smaller expansion size (P < .001), and AAO (P < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion. CONCLUSION: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.

Humans↗
PubMed1993

Ocular adnexal lymphoproliferative lesions.

Ocular adnexal lymphoproliferative lesions consist of a spectrum of disease entities, including reactive lymphoid hyperplasia, atypical lymphoid hyperplasia, and lymphoma. No clinical or radiologic criteria facilitate a distinction among these lymphoproliferative lesions. The two hyperplastic processes may evolve to localized or systemic lymphoma. A similar pattern is evident in other mucosa-associated lymphoid tumors elsewhere in the body. Most ocular adnexal lymphomas are small lymphocytic non-Hodgkin's tumors with an indolent course; frequently, they remain localized to the ocular adnexa. In comparison, intermediate- and high-grade lymphomas are less common in the ocular adnexa but more aggressive. An approach to the diagnosis and treatment of these complex entities is suggested. Despite new pathologic classification schemes, immunophenotypic labeling, and molecular genetic analysis, the prognosis for patients with small-cell lymphoma in the ocular adnexa is difficult to predict.

Conjunctiva↗
PubMed2003

Macroevolutionary relationships of species of Drosophila melanogaster group based on mtDNA sequences.

The phylogenetic relationships among the Drosophila melanogaster group species were analyzed using approximately 1700 nucleotide-long sequences of the mitochondrial DNA. Phylogenetic analysis was performed using this region consisting of a part of the cytochrome b (cytb) coding gene, the entire coding sequences of tRNA-Leu, tRNA-Ser and the first subunit of NADH dehydrogenase (NADH1), and a part of the 16S-rRNA gene. The study of these sequences showed that this region of mtDNA is very invariable, as regards with the type of the genes that it contains, as well as the order that they are located on it. The resulting phylogenetic trees reveal a topology that separates the species into three main ancestral lines, leading to the following subgroups: (a) ananassae subgroup, (b) montium subgroup, and (c) melanogaster and Oriental subgroups. The inferred topology complements and generally agrees with previously proposed classifications based on morphological and molecular data.

Animals↗
PubMed2001

Chronic lymphocytic leukemia (CLL) is rare, but the proportion of T-CLL is high in Japan.

Chronic lymphocytic leukemia (CLL) is a rare disease in Japan. Recent advances in molecular biology, diagnostic criteria and classification of CLL have reinforced the concept of each category of CLL as a distinct entity. Since there have been no recent studies on the incidence and prevalence of CLL in Japan, the Kyushu Hematology Organization for Treatment (K-HOT) Study Group conducted two studies of CLL. One study is a prospective registration of newly diagnosed hematological disorders, which gave us some idea of the incidence of CLL in our region (Kyushu island) where adult T-cell leukemia is endemic. A total of 677 patients with hematological disorders were registered over a 6-month period and 11 patients were diagnosed as having CLL among 182 leukemia patients. This amounts to 6% of all leukemias, which is twice as frequent as previously reported in Japan. The other study is a retrospective analysis of CLL. Eleven institutions of the K-HOT Group analysed their diagnostic records of chronic lymphoid leukemia, and 145 patients with CLL were found over a period of 3-12 yr. After the data were reviewed 11 patients were excluded through having a different type of leukemia. The proportion of chronic B-cell lymphoid leukemia was 73% (98/134), while that of T-cell leukemia was 18% (24/134). The proportion of T-cell chronic leukemia was 5-6 times higher than that in Western countries. Two institutions had a complete database on hematological disorders. From this database, the annual incidence of CLL was estimated to be 0.48 per 100 000. Thus, the incidence of CLL in Japan is at least 4-5 times lower than that in Western countries, suggesting that chronic B-cell leukemia is really rare, but chronic leukemia of T-cell lineage develops in Japan as frequently as in Western societies. Further investigation is required to delineate why the incidence of B-CLL is so low in Japan.

Adult↗