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PubMed1990

Nitrosoureas from chemist to physician: classification and recent approaches to drug design.

Molecular design of chemotherapeutic nitrosoureas is reviewed in the light of a chemical classification of N-(2-chloroethyl)-N-nitrosoureas (CNUs), particularly those recently introduced and earlier compounds tested in the clinic. Of the six categories, three are rather arbitrarily based on physicochemical properties: the original, lipid-soluble drugs, water-soluble sugar derivatives, and amides of intermediate character. Others deal with more complex drug designs incorporating antimetabolites (5-fluorouracil), steroids, redox delivery systems, or hypoxia-selective 2-nitroimidazoles. Current attempts to modify the standard 2-chloroethyl group, with implications for interstrand cross-linking of DNA, are considered. Two unfortunate factors influencing the choice of drugs for clinical trial have been prejudice from the physician and commercial interests. The latter requires no further comment, but a strong plea is made for recognition of the CNU group as one of comparatively few valuable tools for rational drug design requiring appropriate pharmacokinetic evaluation, rather than as a somewhat boring hallmark of repetitive chemists.

Antineoplastic Agents↗
PubMed2001

Divergence pattern of animal gene families and relationship with the Cambrian explosion.

There are many gene families that are specific to multicellular animals. These have either diverged from ancestral genes that are shared with fungi and/or plants or evolved from an ancestral gene unique to animals. The evolution of gene families involved in cell-cell communication and developmental control has been studied to establish whether the number of member genes increased dramatically immediately prior to or in concert with the Cambrian explosion. A molecular phylogeny-based analysis of several animal-specific gene families has revealed that gene diversification by duplication occurred during two active periods interrupted by a long intervening quiescent period. Intriguingly, the Cambrian explosion is situated in the silent period, indicating that there is no direct link between the first burst of gene diversification and the Cambrian explosion itself. The importance of gene recruitment as a possible molecular mechanism for morphological diversity, and its possible role for the Cambrian explosion, are discussed.

Animals↗
PubMed2006

Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau.

The majority of neurodegenerative diseases are characterized by the deposition of insoluble protein in cells of the neuromuscular system. Advances in molecular neuropathology have allowed a classification system of neurodegenerative diseases based on this protein accumulation. Microtubule-associated tau is one protein that has important functions in healthy neurons, but forms insoluble deposits in diseases now known collectively as tauopathies. Tauopathies encompass more than 20 clinicopathological entities, including Alzheimer's disease, the most common tauopathy, progressive supranuclear palsy, Pick's disease, corticobasal degeneration and post-encephalitic parkinsonism. There are important clinical, pathological, biochemical and genetic similarities in the range of these diseases and they have helped to advance our understanding of the aetiological factors that initiate neurodegeneration and tau accumulation. This review examines the important clinical features of the most prevalent tauopathies and the molecular and pathological features that underpin the classification system.

Animals↗
PubMed2005

Gliomas: advances in molecular analysis and characterization.

BACKGROUND: Gliomas represent the most common primary brain tumor. Despite recent advances in diagnostic imaging, neurosurgical technique, radiation therapy, and chemotherapy, significant advances in accurate prognosis and improved survival have not been achieved. Nevertheless, new developments in molecular biology could have potential impact on the clinical management of patients with these brain tumors. This review will describe the technological advances being used to enrich the classification of gliomas, present specific studies that have successfully used the new technologies to identify molecular subtypes of glioblastoma, and discuss the implications of such enhanced classification and molecular characterizations for the prediction of therapeutic response and the design of future brain tumor therapies. RESULTS: Innovative techniques using complementary DNA and oligonucleotide microarrays (gene chips), tissue microarrays (tissue chips), and differential immunoabsorption have provided high throughput and potentially comprehensive approaches for the molecular characterization of human gliomas. Alterations of several tumor suppressor genes and oncogenes have already been identified as being critical to glioma transformation and progression. These approaches have led to the subclassification of glioblastoma multiforme into distinct subtypes based on the molecular signatures of the tumors. CONCLUSIONS: Classifications of gliomas can now be enhanced with new techniques for comprehensive molecular characterization. Improved and efficient molecular profiling of brain tumors is advancing diagnosis/prognosis and identifying targets for novel and rational therapeutic approaches. Neurosurgeons and neuro-oncologists should be aware of these new developments so they can better advise and treat their patients.

Biomarkers, Tumor↗
PubMed1998

Colicins--exocellular lethal proteins of Escherichia coli.

Colicins are toxic exoproteins produced by bacteria of colicinogenic strains of Escherichia coli and some related species of Enterobacteriaceae, during the growth of their cultures. They inhibit sensitive bacteria of the same family. About 35% E. coli strains appearing in human intestinal tract are colicinogenic. Synthesis of colicins is coded by genes located on Col plasmids. Until now more than 34 types of colicins have been described, 21 of them in greater detail, viz. colicins A, B, D, E1-E9, Ia, Ib, JS, K, M, N, U, 5, 10. In general, their interaction with sensitive bacteria includes three steps: (1) binding of the colicin molecule to a specific receptor in the bacterial outer membrane; (2) its translocation through the cell envelope; and (3) its lethal interaction with the specific molecular target in the cell. The classification of colicins is based on differences in the molecular events of these three steps.

Colicins↗
PubMed2004

Molecular properties of WHO essential drugs and provisional biopharmaceutical classification.

The purpose of this study is to provisionally classify, based on the Biopharmaceutics Classification System (BCS), drugs in immediate-release dosage forms that appear on the World Health Organization (WHO) Essential Drug List. The classification in this report is based on the aqueous solubility of the drugs reported in commonly available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. The WHO Essential Drug List consists of a total of 325 medicines and 260 drugs, of which 123 are oral drugs in immediate-release (IR) products. Drugs with dose numbers less than or equal to unity [Do = (maximum dose strength/250 mL)/solubility < or = 1] are defined as high-solubility drugs. Drug solubility for the uncharged, lowest-solubility form reported in the Merck Index or USP was used. Of the 123 WHO oral drugs in immediate-release dosage forms, 67% (82) were determined to be high-solubility drugs. The classification of permeability is based on correlations of human intestinal permeability of 29 reference drugs with the estimated log P or CLogP lipophilicity values. Metoprolol was chosen as the reference compound for permeability and log P or CLogP. Log P and CLogP were linearly correlated (r2 = 0.78) for 104 drugs. A total of 53 (43.1%) and 62 (50.4%) drugs on the WHO list exhibited log P and CLogP estimates, respectively, that were greater than or equal to the corresponding metoprolol value and are classified as high-permeability drugs. The percentages of the drugs in immediate-release dosage forms that were classified as BCS Class 1, Class 2, Class 3, and Class 4 drugs using dose number and log Pwere as follows: 23.6% in Class 1, 17.1% in Class 2, 31.7% in Class 3, and 10.6% in Class 4. The remaining 17.1% of the drugs could not be classified because of the inability to calculate log P values because of missing fragments. The corresponding percentages in the various BCS classes with dose number and CLogP criteria were similar: 28.5% in Class 1, 19.5% in Class 2, 35.0% in Class 3, and 9.8% in Class 4. The remaining 7.3% of the drugs could not be classified since CLogP could not be calculated. These results suggest that a satisfactory bioequivalence (BE) test for more than 55% of the high-solubility Class 1 and Class 3 drug products on the WHO Essential Drug List may be based on an in vitro dissolution test. The use of more easily implemented, routinely monitored, and reliable in vitro dissolution tests can ensure the clinical performance of drug products that appear on the WHO Essential Medicines List.

Administration, Oral↗
PubMed2003

Multiple fuzzy neural network system for outcome prediction and classification of 220 lymphoma patients on the basis of molecular profiling.

A fuzzy neural network (FNN) using gene expression profile data can select combinations of genes from thousands of genes, and is applicable to predict outcome for cancer patients after chemotherapy. However, wide clinical heterogeneity reduces the accuracy of prediction. To overcome this problem, we have proposed an FNN system based on majoritarian decision using multiple noninferior models. We used transcriptional profiling data, which were obtained from "Lymphochip" DNA microarrays (http://llmpp.nih.gov/DLBCL), reported by Rosenwald (N Engl J Med 2002; 346: 1937-47). When the data were analyzed by our FNN system, accuracy (73.4%) of outcome prediction using only 1 FNN model with 4 genes was higher than that (68.5%) of the Cox model using 17 genes. Higher accuracy (91%) was obtained when an FNN system with 9 noninferior models, consisting of 35 independent genes, was used. The genes selected by the system included genes that are informative in the prognosis of Diffuse large B-cell lymphoma (DLBCL), such as genes showing an expression pattern similar to that of CD10 and BCL-6 or similar to that of IRF-4 and BCL-4. We classified 220 DLBCL patients into 5 groups using the prediction results of 9 FNN models. These groups may correspond to DLBCL subtypes. In group A containing half of the 220 patients, patients with poor outcome were found to satisfy 2 rules, i.e., high expression of MAX dimerization with high expression of unknown A (LC_26146), or high expression of MAX dimerization with low expression of unknown B (LC_33144). The present paper is the first to describe the multiple noninferior FNN modeling system. This system is a powerful tool for predicting outcome and classifying patients, and is applicable to other heterogeneous diseases.

Cluster Analysis↗
PubMed1993

[Molecular epidemiology of Neisseria gonorrhoeae: typing with combined auxotype/serovar classification].

Auxotyping or determination of serovars of N. gonorrhoeae used separately can be for a limited differentiation of strains only. Combined auxotype/serovar (A/S)-classification was examined for its discriminatory ability on 360 gonococcal strains isolated over 9 years in the area of Heidelberg. The prototrophic, prolin requiring and (P)AH(U)-auxotype were the 3 most frequent auxotypes. 33 different serovars were identified. Protein-IB-serovars dominated by 75%. IB-3, IB-2 and IA-1/2 were the most frequent serovars. The (P)AH(U) auxotype is statistically significant associated with serovar IA-1/2, the PA(U) auxotype with serovar IB-2/16 and the prolin requiring auxotype with serovar IB-1. Combined typing resulted in 68 different A/S classes. The 3 most frequent classes were Proto/IB-3, (P)AH(U)/IA-1/2 and Proto/IB-2/16. The number of the A/S classes identified per year rose generally with the number of the isolated strains. Our data show the heterogeneity and dynamics of a gonococcal population. A/S classification permits the epidemiological differentiation of a gonococcal population in endemic, transient and microepidemic strains.

Antibodies, Monoclonal↗
PubMed2003

Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma.

Molecular mechanisms through which MYCN expression contributes to the malignant phenotype of neuroblastoma are unknown. We performed a genome-widegene expression analysis of 40 well-characterized neuroblastic tumors and 12 cell lines to identify genes and biological pathways associated with MYCN expression. Gene expression was validated by reverse transcription-PCR and immunohistochemistry using tissue arrays. Two hundred twenty-two of 62,839 oligonucleotide probe sets detected expression of genes that were strongly associated with MYCN expression. Differentially expressed genes included examples of known oncogenes, genes associated with neural differentiation, and genes related to cell proliferation. Expression of a subset of these genes was altered after transfection of a neuroblastoma cell line, SK-N-ER, with a MYCN expressing gene construct when protein synthesis was inhibited and have consensus MYCN binding E-box sequences in their promotor regions, suggesting they represent direct targets. Several novel genes/expressed sequences were identified as overexpressed and most likely coamplified with MYCN in a subset of cases. A classification model to identify neuroblastomas with high levels of MYCN expression was developed based on expression profiles. The identification of coexpressed and coamplified genes associated with MYCN overexpression in neuroblastoma suggests biochemical pathways that contribute to the malignant behavior of these tumors and forms a basis for molecular classification.

Cell Nucleus↗
PubMed1996

The World Health Organization classification of adenohypophysial neoplasms. A proposed five-tier scheme.

BACKGROUND: Although numerous attempts have been made, the classification of pituitary neoplasms remains controversial. METHODS: The present proposal is based on correlative clinical and pathologic (histologic, immunocytochemical, and electron microscopic) studies of more than 8000 surgically removed human pituitary tumors. RESULTS: Anterior pituitary tumors have been variously classified on the basis of their clinical presentation, biochemical findings, histology (growth pattern, tinctorial characteristics), proliferation indices, immunocytochemical profile, and ultrastructural features. Herein we propose a five-tier classification, clinicopathologic in nature, which focuses on endocrine activity, imaging, operative findings, histology, immunocytochemistry, and ultrastructure. The integration of these five complementary approaches into what is fundamentally a pathologic classification is as practical as it is novel. Its importance lies in the fact that the collected data provide valuable information to the clinical endocrinologist, neurosurgeon, and oncologist involved in the assessment of a tumor's biologic behavior, growth potential, therapeutic responsiveness, and prognosis. Due to financial restraints, lack of facilities, and unavailability of well trained personnel, we realize that at present the five approaches cannot be fully implemented in all institutions. Nonetheless, clinical and biochemical data, imaging, and operative findings, as well as basic histologic parameters are generally readily available. Collectively they are indispensable in establishing the correct diagnosis and in directing patient management. Conversely, the cost-effectiveness of immunocytochemistry and electron microscopy is debatable in that their performance and interpretation requires time, financial resources, and expertise. Nonetheless, it should be clear that any correlation between endocrine activity, growth potential, morphologic features, immunocytochemical profile, and ultrastructural features provides greater insight into the pathobiology of adenohypophysial tumors than is gained by routine histology alone. Thus we feel justified in including immunocytochemical and ultrastructural investigation of pituitary tumors in a modern classification. At present, more sophisticated molecular biologic methods represent investigative tools that play no significant role in the classification. CONCLUSIONS: A five-tier classification of adenohypophysial neoplasms based on clinical and biochemical results, imaging, operative findings, histology, immunocytochemistry, and electron microscopy is proposed. It is recommended to the World Health Organization for acceptance.

Humans↗
PubMed2002

Large-scale gene expression analysis in molecular target discovery.

The evolution of simple arrays consisting of a few genes to ones composed of thousands of genes and/or ESTs has allowed investigators unprecedented views of the molecular mechanisms within cells. Due to the enormous quantities of information derived from microarray analysis, new types of problems have surfaced, such as where to store all of the data. The ability to solve database or statistical problems has required the bench biologist to collaborate with database developers, software designers and statisticians to determine solutions for storage, analysis and interpretation of microarray data. The collaborative effort between these extremely diverse disciplines has led to the development of creative database query and gene expression analysis tools, producing significant reductions in the time required by researchers to filter through the datasets and discover the key processes perturbed by the diseases of interest. Both unsupervised and supervised analysis methods have been applied to gene expression data leading to the discovery of novel therapeutic targets and diagnostic markers. Furthermore, tumor classification based on their respective molecular fingerprints has led to the classification of cancer subtypes and the discovery of novel molecular taxonomies that may eventually lead to improved patient stratification and superior therapeutic strategies.

Databases, Factual↗
PubMed1995

Does early-onset Alzheimer disease constitute a distinct subtype? The contribution of molecular genetics.

Alzheimer disease (AD) is a clinical and pathologic diagnosis and refers to the findings of neurofibrillary tangles and amyloid plaques in the brain of a patient with dementia. Clinically it is recognized that there are familial and sporadic forms, with further division into those with presenile and senile onset. Clinical, neuroimaging, neuropathological, and neurochemical studies have attempted to identify differences between cases with an earlier and later onset, but have not identified a categorical biologic difference between the two groups. Recent advances in the molecular genetics of familial Alzheimer disease (FAD) and the discovery of defined genetic abnormalities have provided a robust approach to distinguishing between early- and late-onset cases within the group of autosomal dominant FAD. The precise biologic classification made possible by molecular genetic analysis of FAD provides a benchmark against which phenotypic differences can be assessed. This article argues that future studies will be able to contrast early-onset familial versus late-onset familial disease, and early-onset familial versus early-onset sporadic disease. Previous reports of phenotypic differences within AD may have been the result of including FAD within early-onset groups, though this remains to be established.

Age of Onset↗
PubMed1988

Molecular modeling of protein structure and function: a bioinformatic approach.

This paper reports on the data/information structure of macromolecules as it extends beyond the three-dimensional conformation to include functional descriptors of biochemical (in vitro) and biological (in vivo) characteristics and as it contrasts with the limitations imposed by the data reduction and data classification techniques of traditional molecular modeling. Methodologies for structure-function representation are presented which are being incorporated within a knowledge-acquisition expert system. Examples of the bioinformatic approach are presented concerning macromolecular recognition by serine proteases and the use of Fourier transform-infrared (FT-IR) spectroscopy for structural assignment and analysis by a novel structure-perturbation approach.

Computer Simulation↗
PubMed1997

[Molecular analysis of glucose-6-dehydrogenase deficiency in Spain].

PURPOSE: G6PD deficiency is the most frequent enzymopathy-producing genetic polymorphism in humans. Up to now, over 400 putative variants of G6PD have been distinguished on the basis of biochemical characterization of the deficient enzyme. Analysis of the G6PD gene has made possible a precise classification of the G6PD molecular variants by identification of about 80 different point mutations causing much of the phenotypic heterogeneity. In the Spanish population, the analysis of G6PD has led to the identification of 15 different point mutations that underlay the phenotypic heterogeneity of G6PD previously reported by biochemical analysis. The purpose of the study has been to identify the genetic mutation responsible of the G6PD deficiency and to improve the knowledge of its genetic homogeneity. PATIENTS AND METHODS: From 50 Spanish males with G6PD deficiency 34 came from out consultation and 16 from the Spanish Study Group on Red Cell Pathology (GEHBTA-Eritropatología) The methods employed included screening of prevalent mutations by ER-PCR, SSCP-PCR, genetic segmentation and biochemical characterization of the deficient enzyme. RESULTS: In 31 cases the mutations were characteristic of the four most frequent polymorphic variants found in Spain (G6PD A-376G/202A, G6PD Mediterranean 563T G6PD Union 1360T and G6PD Seattle 344C). Since these mutations either create or abolish a specific site recognized by a restriction endonuclease (RE), they can be rapidly detected by RE digestion of a PCR-amplified product (PCR-RE). In patients where none of these mutations were present (17 cases), the G6PD gene was subjected to PCR single-strand conformation polymorphism (PCR-SSCP) analysis combined with direct PCR-sequencing. By using this procedure, 9 new mutations have been identified, five of them have been also found in other geographical areas and were associated with favism (G6PD A-376G/968C, G6PD Santamaria 376G/542T, G6PD Aures 143C and G6PD Chatham 1003A) or chronic haemolytic anaemia (G6PD Tomah 1153C). The other four mutations are unique and not reported so far: Three of them are associated with favism (G6PD Málaga 542T, G6PD Murcia 209G and G6PD Valladolid 406T) and one with chronic haemolytic anaemia (G6PD Madrid 1155G). The remaining eight cases are under study. CONCLUSION: The present study confirms the marked genetic heterogeneity of G6PD deficiency in Spain and demonstrate that the PCR-RE analysis is an easy tool for rapid diagnosis of the molecular defect in subjects with the common forms of G6PD deficiency. Furthermore the fact that G6PD A-376G/202A is the most common variant within Spanish population and the finding of G6PD Aures 43C and G6PD Santamaría 76G/542T, who are polymorphic in Algeria is consistent with a significant gene flow from Africa to Europe through Spain.

Africa, Northern↗
PubMed1998

Species-specific primers resolve members of Fusarium section Fusarium. Taxonomic status of the edible "Quorn" fungus reevaluated.

Sixty-seven authentic isolates, representing six species from Fusarium section Fusarium (= section Discolor) were subjected to random amplified polymorphic DNA (RAPD) analysis and polymerase chain reaction using species-specific primers. Remarkably uniform RAPD banding patterns were obtained intraspecifically, irrespective of the geographical origin of the isolates or the host/substratum from which they were isolated. Isolates were also assessed for colony characteristics when grown on a defined minimal medium. The Quorn strain (ATCC 20334; previously considered to be F. graminearum) matched the F. venenatum strains exclusively in RAPD profile. In addition, equivalently sized DNA fragments amplified from ATCC 20334 and two authentic F. venenatum strains were identical with respect to DNA sequence. Our molecular and morphological data support the identification of the Quorn strain as F. venenatum Nirenberg (= F. sambucinum Fuckel sensu lato).

Base Sequence↗
PubMed2006

A gzip-based algorithm to identify bacterial families by 16S rRNA.

AIMS: Microbial family identification of 16S rDNA sequences by applying a strategy based on algorithms for data compression. METHODS AND RESULTS: Perl scripts were developed to analyse similarities in microbial sequences, based on a gzip data compression technique. For each bacterial family (n=196) a 16S rRNA reference file was constructed to compare new queries looking at compression performance. An online user-friendly bioinformatics tool was built up to attribute a bacterial family to a 16S rRNA sequence. It was successfully applied to recognize different bacterial families, including Legionellaceae, Bacillaceae, Enterobacteriaceae, Acetobacteriaceae and Rhizobiaceae. The percentage of positive identifications is higher than 95% for fragments over 450 bp. CONCLUSIONS: A new bioinformatics approach has been developed to assign a taxonomic classification to a 16SrDNA sequence. An online tool provides quick and easy sequence attribution. The general principle can be applied to other genes of taxonomic interest. SIGNIFICANCE AND IMPACT OF THE STUDY: Availability of simple bioinformatics tools can support the development of molecular-based analysis and classification of bacteria, especially for environmental or uncultured strains.

Algorithms↗
PubMed2003

Biochemical properties and substrate specificities of alkaline and histidine acid phytases.

Phytases are a special class of phosphatase that catalyze the sequential hydrolysis of phytate to less-phosphorylated myo-inositol derivatives and inorganic phosphate. Phytases are added to animal feedstuff to reduce phosphate pollution in the environment, since monogastric animals such as pigs, poultry, and fish are unable to metabolize phytate. Based on biochemical properties and amino acid sequence alignment, phytases can be categorized into two major classes, the histidine acid phytases and the alkaline phytases. The histidine acid phosphatase class shows broad substrate specificity and hydrolyzes metal-free phytate at the acidic pH range and produces myo-inositol monophosphate as the final product. In contrast, the alkaline phytase class exhibits strict substrate specificity for the calcium-phytate complex and produces myo-inositol trisphosphate as the final product. This review describes recent findings that present novel viewpoints concerning the molecular basis of phytase classification.

6-Phytase↗