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Overview of posttransplant B-cell lymphoproliferative disorders.

Epstein-Barr virus-associated B-cell lymphoproliferations are a serious complication of organ or bone marrow transplantation whose incidence is strongly influenced by a number of risk factors. The disease represents a model of Epstein-Barr virus-driven lymphoid neoplasia in the setting of immunodeficiency. The incidence and pathogenesis of posttransplant lymphoproliferations are examined in relation to the nature of the transplanted organ, the Epstein-Barr virus infection, and the use of specific immunosuppressive regimens. Pathologic classifications and molecular mechanisms for neoplasia are reviewed. Clinical manifestations, pathologic features, and diagnostic considerations are summarized, with emphasis on those aspects that differ significantly from classic non-Hodgkin's lymphoma. Existing data regarding treatment are reviewed, including reduction in immunosuppression, surgery, radiation, chemotherapy, interferon-alpha, monoclonal anti-B-cell antibodies, and T-cell therapy. A basis for the selection of therapeutic options is suggested.

Cell Transformation, Neoplastic↗

[Advancement on neurotransmitter transporters].

The neurotransmitter transporter (NTT), a kind of glycoprotein situating on the presynaptic membrane, glial membrane, or vesicle membrane, has become the focusing point of neuroscience research in recent years. They could combine selectively with transmitters released into synaptic cleft and carry them back into cells to aid the termination of synaptic transmission. In this way, NTT took an important part in modulation of information between neurons. Study on NTT has not been reported domestically. This article reviewed recent studies on molecular structure, classification, study methods, distribution, function, modulating factors and gene modulation, focus of study and also unresolved problems of NTT.

ATP-Binding Cassette Transporters↗

[Allergies associated with both food and pollen].

Recent progress in understanding structural relationships between allergens has allowed their classification into molecular families. Proteins belonging to a molecular family often show some degree of IgE cross-reactivity. These cross-reactions can lead to a clinical association like birch-apple syndrome whose basis is a sensitization to a PR-10 protein (birch pollen Bet v 1) and then oral symptoms in contact to apple Mal d 1, another PR-10 family member. Food allergens implicated into pollen-food allergy syndromes differ from those linked to crustacea or milk cross-allergies: they seem unable to sensitize the patient through oral route. As a result, they most often induce weaker clinical reactions than complete allergens like those present in shrimp or cow milk. Numerous molecular families have been isolated from pollens. PR-10 and profilins have a well established role in inducing clinical reactions to food like fruits and vegetables. Some molecular families need more studies to delineate their true impact on pollen-driven food reactions: polygalacturonases, pectate lyases, isoflavone reductases, thaumatin-like, cyclophilins.... Others are found in pollen but not in eaten products: 2-EF-hand calcium binding proteins, beta expansins,... Lipid transfer proteins (LTP) are widespread plant food allergens (e.g. in peach): these proteins seem able to directly sensitize the patient through oral route. But recent data have suggested a possible additional effect of some LTP present in pollens (mugwort, olive, pellitory).

Allergens↗

Anomalies of cerebral structures in acranial neonates.

Eleven cases of newborns with acrania and macroscopically diagnosed anencephaly were neuropathologically examined. They presented changes in which 1 group corresponded to the diagnosis of aprosencephaly. In the second group, the development of prosencephalic structures was more advanced. The pathomechanism of the observed anomalies was analyzed in relation to data provided by molecular-genetic classification of nervous system malformations, but that did not exclude the influence of eventual extrinsic factors.

Abnormalities, Multiple↗

Presence of insertion sequences (IS elements) in group B streptococci of bovine origin.

BACKGROUND & OBJECTIVES: Streptococcus agalactiae (group B streptococci, GBS) is one of the leading causative agents of human and animal infections. Recently it was demonstrated that integration of different IS elements could inactivate some of the GBS virulence properties. The presence of IS elements in human isolates has been studied while the bovine isolates were not investigated till now. The objective of the study was to perform IS analysis of a large number of bovine GBS and to use the IS elements for classification and molecular epidemiology of GBS strains. METHODS: A total of 101 GBS isolates obtained from the dairy cows were tested. These were analyzed by PCR and multiplex PCR. Southern hybridization was accomplished with the Enzo(TM) DNA Labeling and Detection Kit. The computer techniques were used for selection of the specific primers and for analysis of the sizes of PCR products. RESULTS: GBS isolates collected at three different dairy farms were studied for the presence of IS elements. Multiplex PCR was used for the fast screening. It was found that IS861 presented in 29 GBS isolates (28.7%), IS1548 in 9 (8.9%), ISSa4 in 48 (47.5%) and IS1381 in 26 isolates (25.7%). A total of 28 bovine GBS isolates (27.7%) did not possess any of the IS elements, 36 (35.6%) possessed, 35 (34.7%) possessed two and 2 (1.9%) possessed three different IS elements. The GBS with four different IS elements were not found. Taken together, 10 different variants of GBS strains were discovered. Two out of 10 variants being specific for 51 isolates (50.5%) were predominant in bovine GBS. The results of the study demonstrated that the presence of IS elements significantly varied in bovine GBS. INTERPRETATION & CONCLUSION: The present data demonstrated that variants of IS elements present in GBS genome could be used as effective criteria for molecular epidemiology. In future this approach could probably be used as an additional tool for the epidemiological control and prevention of other bacterial infections.

Animals↗

[Actinic keratosis and development of cutaneous squamous cell carcinoma].

BACKGROUND: Actinic keratosis is a common sun-induced skin disease. For many years there has been a great deal of discussion of the term used for the disease and of its classification. Recent molecular studies indicate an association between actinic keratosis and squamous cell carcinoma. MATERIAL AND METHODS: Review of recent reports on histological, molecular, biochemical and clinical findings in actinic keratosis and cutaneous squamous cell carcinoma. RESULTS AND INTERPRETATION: The morphology of atypical cells in both actinic keratosis and squamous cell carcinoma is identical. The risk of progression to squamous cell carcinoma is minimal, but up to 60% of squamous cell carcinoma cases begin as actinic keratosis. Regression of actinic keratosis occurs when sun exposure is decreased. Examination of possible chromosome aberrations and gene mutations in both actinic keratosis and squamous cell carcinoma reveals similar patterns, including the same mutation in the tumour suppressor gene TP53. Recent studies indicate that actinic keratosis is the earliest manifestation of a potentially malignant disease similar to carcinoma in situ in cervix uteri. Thus, actinic keratosis requires careful diagnosis and follow up.

Carcinoma in Situ↗

[Algorithms for constructing phylogenetic trees of maximum topological similarity].

The paper concerns the practical realization of the maximum topologic similarity principle for phylogenetic reconstruction. This novel principle is described in the accompanying paper. Two algorithms that were embodied in the computer program allow one to find out the unique tree in case when source data admit the existence of such tree. In case if numerous parallel mutations make such precise realization impossible, algorithms allow one to obtain approximations to the maximum topologic similarity trees with a high computation efficiency. Examples illustrating use of these algorithms, as well as discussion of biological consistency of the novel concept are presented.

Algorithms↗

[Substrate specificity of the beta-lactamases found in a number of clinical strains of gram-negative bacteria].

The substrate profiles of beta-lactamases defected in 46 clinical polyresistant strains of gram-negative bacteria were determined. By the substrate profile and sensitivity to inhibitors (dicloxacillin and p-CMB) beta-lactamases were considered to belong to classes I, II, III, IV and V of the Richmond classification. The molecular weights of the enzymes were measured. Enterobacter aerogenes 6803, Enterobacter aerogenes 11030 and Klebsiella pneumoniae 970 produced simultaneously two beta-lactamases belonging to different classes. beta-Lactamases of classes I and III were detected in the cells of Enterobacter aerogenes 6803. The cells of Enterobacter aerogenes 11030 contained beta-lactamases of classes V and III and the cells of Klebsiella pneumonia 970 beta-lactamases of classes II and III. Therefore, in all the cases one of beta-lactamases belonged to the class III enzyme close to TEM beta-lactamases by its substrate profile, molecular weight and sensitivity to the inhibitors. Cephalexin and dicloxacillin were most frequently stable to the effect of the above beta-lactamases. The enzymes from 26 strains did not hydrolyse or hydrolysed slightly cephalexin and the enzymes from 19 strains did not hydrolyse of hydrolysed slightly dicloxacillin.

Anti-Bacterial Agents↗

R factors: plasmids conferring resistance to antibacterial agents.

Antibiotic sensitivity and resistance are often under the control of the bacterial chromosome. Frequently, however, an organism may exhibit resistance to one or several antibiotics as a dominant character determined by genes located on a plasmid, a relatively small, circular DNA molecule which replicates, with some degree of autonomy, in the bacterial cytoplasm. Such plasmids, termed drug-resistance (R) factors, generally also specify the formation of sex pili, filamentous appendages on the cell surface. These promote bacterial conjugation, and hence permit the transfer of a copy of the plasmid from the resistant organism to one which may previously have been drug-sensitive. Each ex-conjugant is then capable of acting as a plasmid donor during subsequent pairings, so that R factors are commonly responsible for the epidemic spread of multiple drug-resistance throughout an entire bacterial population. This can present serious problems in antibiotic therapy, particularly as plasmids are often transmissible between organisms of different species, and even different genera. The molecular nature, classification and behaviour of R factors is discussed.

Bacteria↗

[Diagnostic approach to von Willebrand's disease in childhood].

Von Willebrand's disease seems to be the most common hereditary bleeding disorder in children. Every form of this disease is based on quantitative or qualitative disorder of von Willebrand's factor influencing adhesion of thrombocytes (primary hemostasis) and stabilization FVIII:C in circulation (secondary hemostasis). We present contemporary knowledge on epidemiologic investigations, molecular biology, classification and rational diagnostic approach to von Willebrand's disease in children. We also report on evaluating laboratory tests' reliability in 51 examined children with von Willebrand's disease. It can be concluded that most laboratory tests are highly specific and significant for diagnosis. Determination of vWF activity has optimal value for establishing laboratory diagnosis of von Willebrand's disease; RIPA and multimer analysis are valuable for subtype classification.

Adolescent↗

Molecular cytogenetics of primary breast cancer by CGH.

Comparative genomic hybridization (CGH) reveals DNA sequence copy number changes that are shared among the different cell subpopulations present in a tumor and may help to delineate the average progression pathways of breast cancer. Previous CGH studies of breast cancer have concentrated on selected subgroups of breast cancer. Here, 55 unselected primary breast carcinomas were analyzed using optimized quality-controlled CGH procedures. Gains of 1q (67%) and 8q (49%) were the most frequent aberrations. Other recurrent gains were found at 33 chromosomal regions, with 16p, 5p12-14, 19q, 11q13-14, 17q12, 17q22-24, 19p, and 20q13 being most often (> 18%) involved. Losses found in > 18% of the tumors involved 8p, 16q, 13q, 17p, 9p, Xq, 6q, 11q, and 18q. The total number of aberrations per tumor was highest in poorly differentiated (P = 0.01) and in DNA aneuploid (P = 0.05) tumors. The high frequency of 1q gains and presence of +1q as the sole abnormality suggest that it is an early genetic event. In contrast, gains of 8q were most common in genetically and phenotypically advanced breast cancers. The vast majority of breast cancers (80%) have gains of 1q, 8q, or both, and 3 changes (+1q, +8q, or -13q) account for 91% of the tumors. In conclusion, CGH results indicate that certain chromosomal imbalances are very often selected for, sometimes in a preferential order, during the progression of breast cancer. Further studies of such common changes may form the basis for a molecular cytogenetic classification of breast cancer.

Adult↗

[Lipidic myopathies].

The lipid storage myopathies are produced by a biochemical defect that directly or indirectly interferes with the metabolism of fatty acids in the muscle fiber. The oxidation of fatty acids is performed by enzymes lying in the mitochondrial membranes and matrix. The phenotype is very similar between the different biochemical defects, presenting with two large groups: One with early-onset, metabolic crisis and multisystemic failure, and one with late-onset, predominant myopathy and myoglobinuria. The diagnosis of these disorders has advanced significatively in the last ten years, permitting their classification at molecular level according to the biochemical and genetic defect.

Carnitine↗

Classification and regression tree analysis for molecular descriptor selection and retention prediction in chromatographic quantitative structure-retention relationship studies.

The use of the classification and regression tree (CART) methodology was studied in a quantitative structure-retention relationship (QSRR) context on a data set consisting of the retentions of 83 structurally diverse drugs on a Unisphere PBD column, using isocratic elutions at pH 11.7. The response (dependent variable) in the tree models consisted of the predicted rention factor (log kw) of the solutes, while a set of 266 molecular descriptors was used as explanatory variables in the tree building. Molecular descriptors related to the hydrophobicity (log P and Hy) and the size (TPC) of the molecules were selected out of these 266 descriptors in order to describe and predict retention. Besides the above mentioned, CART was also able to select hydrogen-bonding and molecular complexity descriptors. Since these variables are expected from QSRR knowledge, it demonstrates the potential of CART as a methodology to understand retention in chromatographic systems. The potential of CART to predict retention and thus occasionally to select an appropriate system for a given mixture was also evaluated. Reasonably good prediction, i.e. only 9% serious misclassification, was observed. Moreover, some of the misclassifications probably are inherent to the data set applied.

Chromatography↗

Preliminary classification of nonmalignant B cell proliferation in Sjögren's syndrome: perspectives on pathobiology and treatment based on an integrated clinico-pathologic and molecular study approach.

A classification of nonmalignant lymphoproliferation in Sjögren's syndrome is presented, based on the results of international meetings regarding Sjögren's syndrome-associated lymphomagenesis and on our results of a clinico-pathologic and molecular study and long-term follow-up in well-characterized patients. Sjögren's syndrome pathobiology has similarities to hepatitis C virus-related B-cell lymphoproliferation. Antigen stimulation with the preferential expansion of rheumatoid factor-positive clones and specific immunoglobulin gene expression and recombination represent key biologic events in lymphoproliferation. This classification is based on the coupling of molecular and histological studies and may result in more selective treatment approaches.

Adult↗

Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors.

Various polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental pollutants, are recognized mutagens and carcinogens. A homogeneous set of mutagenicity data (TA98 and TA100,+S9) for 32 benzocyclopentaphenanthrenes/chrysenes was modeled by the quantitative structure-activity relationship classification methods k-nearest neighbor and classification and regression tree, using theoretical holistic molecular descriptors. Genetic algorithm provided the selection of the best subset of variables for modeling mutagenicity. The models were validated by leave-one-out and leave-50%-out approaches and have good performance, with sensitivity and specificity ranges of 90-100%. Mutagenicity assessment for these PAHs requires only a few theoretical descriptors of their molecular structure.

Environmental Pollutants↗

[Different phenotypes of Charcot-Marie-Tooth disease caused by mutations in the same gene. Are classical criteria for classification still valid?].

Molecular genetic research is leading to the continuous discovery of new genes and protein involved in peripheral nerves function. Simultaneously, extended clinical, neurophysiological and pathological research has yielded new genotype-phenotype correlation on Charcot-Marie-Tooth disease (CMT). This has made it possible to know that several genes can cause both demyelinating (CMT1) and axonal (CMT2) phenotypes. Those observations have questioned the validity of some current criteria for CMT classification and raise the need for new strategies for diagnosis. The discovery of Schwann cell-axon interaction is a challenge for coming years. In this review, we extensively analyzed mutations of genes that give rise to CMT1 or CMT2 phenotypes. There are at least three forms of genetic variability. MPZ gene mutations yield a real allelism, that is, CMT1 or CMT phenotypes associated to specific mutation by site or quality. GADP1 and probably NF-L gene manifest different phenotypes but only in terms of nerve conduction velocity (CV). Evidence is provided that indicates that CV reduction in GADP-1 neuropathy may be the result of axonal loss. Finally a third form of variability is present in CMTX due to the degree of clinical expression in females related with the inactivation of chromosome X.

Adaptor Proteins, Signal Transducing↗

Structural classification of protein kinases using 3D molecular interaction field analysis of their ligand binding sites: target family landscapes.

Protein kinases are critical components of signaling pathways and trigger various biological events. Several members of this superfamily are interesting targets for novel therapeutic approaches. All known eukaryotic protein kinases exhibit a conserved catalytic core domain with an adenosine 5'-triphosphate (ATP) binding site, which often is targeted in drug discovery programs. However, as ATP is common to kinases and other proteins, specific protein-ligand interactions are crucial prerequisites for valuable ATP site-directed ligands. In the present study, a set of 26 X-ray structures of eukaryotic protein kinases were classified into subfamilies with similar protein-ligand interactions in the ATP binding site using a chemometrical approach based on principal component analysis (PCA) and consensus PCA. This classification does not rely on protein sequence similarities, as descriptors are derived from three-dimensional (3D) binding site information only computed using GRID molecular interaction fields. The resulting classification, which we refer to as "target family landscape", lead to the identification of common binding pattern and specific interaction sites for particular kinase subfamilies. Moreover, those findings are in good agreement with experimental selectivity profiles for a series of 2,6,9-substituted purines as CDK inhibitors. Their interpretation in structural terms unveiled favorable substitutions toward selective CDK inhibitors and thus allowed for a rational design of specific ligands with minimized side effects. Additional 3D-quantitative structure-activity relationship (QSAR) analyses of a larger set of CDK-directed purines lead to the identification of essential structural requirements for affinity in this CDK ATP binding site. The combined interpretation of 3D-QSAR and the kinase target family landscape provides a consistent view to protein-ligand interactions, which are both favorable for affinity and selectivity in this important subfamily.

Binding Sites↗