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PubMed2004

Gene-expression profiling reveals distinct expression patterns for Classic versus Variant Merkel cell phenotypes and new classifier genes to distinguish Merkel cell from small-cell lung carcinoma.

Merkel cell carcinoma (MCC) is a rare aggressive skin tumor which shares histopathological and genetic features with small-cell lung carcinoma (SCLC), both are of neuroendocrine origin. Comparable to SCLC, MCC cell lines are classified into two different biochemical subgroups designated as 'Classic' and 'Variant'. With the aim to identify typical gene-expression signatures associated with these phenotypically different MCC cell lines subgroups and to search for differentially expressed genes between MCC and SCLC, we used cDNA arrays to profile 10 MCC cell lines and four SCLC cell lines. Using significance analysis of microarrays, we defined a set of 76 differentially expressed genes that allowed unequivocal identification of Classic and Variant MCC subgroups. We assume that the differential expression levels of some of these genes reflect, analogous to SCLC, the different biological and clinical properties of Classic and Variant MCC phenotypes. Therefore, they may serve as useful prognostic markers and potential targets for the development of new therapeutic interventions specific for each subgroup. Moreover, our analysis identified 17 powerful classifier genes capable of discriminating MCC from SCLC. Real-time quantitative RT-PCR analysis of these genes on 26 additional MCC and SCLC samples confirmed their diagnostic classification potential, opening opportunities for new investigations into these aggressive cancers.

Biomarkers, Tumor↗
PubMed1997

Tissue culture adaptation of natural isolates of simian virus 40: changes occur in viral regulatory region but not in carboxy-terminal domain of large T-antigen.

The regulatory region of natural isolates of simian virus 40 (SV40) is different from that of laboratory-adapted strains of the virus. The latter have a nucleotide sequence duplication within the enhancer region which varies slightly with each strain, whereas the duplication is lacking in fresh isolates of SV40, which contain an 'archetypal' regulatory region. Many isolates also display nucleotide differences in the DNA encoding the carboxy terminus of large tumour antigen (T-ag). To determine whether genetic changes in these two regions of the SV40 genome were detectable during laboratory adaptation and long-term passage, low-passage virus stocks of two laboratory strains which had detailed passage histories spanning more than 25 years (Baylor strain and VA45-54) were analysed using PCR, cloning and sequencing assays. Both laboratory and archetypal regulatory regions were present in low-passage stocks. Following duplication in the regulatory region, no additional changes were detectable. The variable region at the T-ag carboxy terminus did not undergo any change with tissue culture passage and may serve as a useful site for taxonomic classification of different strains of SV40. Cloned genomes containing single or duplicated enhancers derived from both SV40 strains were viable in CV-1 cells. Attempts to induce regulatory region duplications by 14 serial passages of SV40 archetypal strains in monkey cells were not successful. The results are compatible with tissue culture adaptation of SV40, reflecting either selection of a rare variant pre-existing in the original sample or generation of a rare regulatory region duplication in infected cells.

Adaptation, Physiological↗
PubMed2005

Variability of the origin of the uterine artery: laparoscopic surgical observation.

AIM: To categorize the surgical anatomic variants of the origins of the uterine arteries and to clarify the difference in the description of the internal iliac artery in the contemporary anthropologic, radiologic and surgical system. METHODS: One hundred women with symptomatic fibroids were treated using retroperitoneal laparoscopic dissection of the uterine vessels (LDUV). Retrospective evaluation of the operative records and videos was carried out. The anatomical classification of Adachi (type I-V) was modified for surgical purposes (type I-IV). RESULTS: Laparoscopic retroperitoneal dissection and LDUV were carried out successfully using an ultrasonic operative technique in all women. The branching of the branches of the internal iliac artery was studied on the right side of the pelvis. Of the 100 uterine arteries that were evaluated, 81% were classifiable types and 19% of surgical dissections were inconclusive. Classification was as follows: type I, 30.8%; type II, 23.4%; type III, 45.6%; and type IV was not found. Modified surgical classification type III (visceral branches arising from the umbilical artery and the internal pudendal artery) was claimed to be statistically the most common type. CONCLUSION: Laparoscopic dissection of the uterine artery close to the origin of the uterine artery can be carried out safely in the most frequent types of surgical classification. The meticulous dissection of the uterine artery in cases in which the uterine artery does not arise typically from an unobliterated segment of the internal iliac artery was recommended.

Arteries↗
PubMed1997

Von Willebrand's disease.

von Willebrand's disease (vWD) arises from abnormalities in von Willebrand factor (vWF), an adhesive glycoprotein uniquely involved in key aspects of both primary and secondary hemostasis. The current classification distinguishes disorders arising from partial (type 1) or complete (type 3) deficiencies and from qualitative defects (type 2). Type 2 vWD is further divided into four subtypes (A, B, N, and M), reflecting distinct classes of functional abnormalities. Mis-sense mutations account for most of type 2 vWD, whereas major disruptions in the vWF gene produce type 3 variants. The molecular basis of type 1 vWD is largely undefined. The laboratory diagnosis of vWD and its several variants is made on the basis of immunologic and functional studies of vWF, factor VIII levels, and specialized electrophoretic analysis (multimer gels). The mainstay of therapy for most patients with vWD in desmopressin, a pharmacologic agent that stimulates the release of endogenous pools of vWF. Cryoprecipitate and selected factor VIII concentrates are useful sources of exogenous vWF for the treatment of patients unresponsive to this desmopressin.

Combined Modality Therapy↗
PubMed1997

Practical method for determination of the U status of S-s- erythrocytes.

Red blood cells (RBCs) lacking S and s blood group antigens are classified as S-s-U- or S-s-U+var but the classification may vary due to the characteristics of anti-U and to the technique used. Tests on RBCs known to lack glycophorin B (GPB) or to possess an altered form of GPB showed that polyethylene glycol-indirect antiglobulin testing or MicroTyping Systems (MTS)-gel techniques can be used as a simple and reliable way to detect RBCs with variant forms of GPB. This approach can be important in the selection of rare RBCs for transfusion to patients with undifferentiated anti-U.

Journal Article↗
PubMed2001

Histologic and immunophenotypic classification of cervical carcinomas by expression of the p53 homologue p63: a study of 250 cases.

Recent studies of the p53 homologue p63 indicate that this gene is preferentially expressed in basal and immature cervical squamous epithelium. This study correlated p63 expression with morphologic phenotype and human papillomavirus (HPV) type in a wide range of cervical neoplasms. Two hundred fifty cases of cervical carcinoma, including squamous cell carcinoma (SCCA; n = 178), adenocarcinoma (ADCA; n = 28), adenosquamous carcinoma (ASCA; n = 8), neuroendocrine carcinoma (NECA; n = 15), and other variant or mixed types (n = 21) were studied. Ninety-seven percent of SCCA, 0% of ADCA, and 0% of SCUC showed strong (>75% v <30%) positivity for p63 (P<.001). p63 sharply distinguished SCCA (p63+) from ADCA (p63-), Large-cell, poorly differentiated carcinomas were distinguished as putative glandular (glassy cell) or squamous (lymphoepithelial-like or spindle cell) types based on p63 staining. Eight (73%) of 11 neuroendocrine tumors tested were chromogranin positive; all showed no or low (<30%) levels of p63 immunostaining. Absence of p63 was also associated with a subset of nonneuroendocrine undifferentiated carcinomas. Transitions from squamous to columnar or undifferentiated morphology coincided with loss of p63 expression. A strong association between HPV 16 and p63 positivity was identified because of the colocalization of both within tumors of squamous phenotype. p63 is a powerful marker for squamous differentiation and, when diffusely expressed, excludes a glandular or neuroendocrine differentiation. p63 may be useful for differentiating pure squamous or glandular from adenosquamous carcinomas, tracking shifts in differentiation within tumors, supporting (by its absence) the diagnosis of neuroendocrine carcinomas, and clarifying the spectrum of poorly differentiated carcinomas lacking either squamous or neuroendocrine differentiation.

Adenocarcinoma↗
PubMed1988

Late Niemann-Pick disease with neurovisceral storage: a classification problem.

A 51 year old man presented in 1969 with slowly progressive cerebellar ataxia of unknown origin. He was admitted to hospital aged 68 after a fall, and a ruptured spleen was removed at laparotomy. Histological analysis of the spleen suggested Niemann-Pick disease, which was subsequently confirmed. He deteriorated and died of bronchopneumonia shortly afterwards: subdural haemorrhage with storage material in neurones was found at necropsy. This late onset case of Niemann-Pick disease with neurovisceral storage is unusual and may represent a variant.

Age Factors↗
PubMed2004

Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature.

Molecular markers (biomarkers) for hepatocellular carcinoma (HCC) metastasis and recurrence could provide additional information to that gained from traditional histopathological features. A large number of biomarkers have been shown to have potential predictive significance. One important aspect of this is to detect the transcripts of tumor-associated antigens (such as AFP, MAGEs, and CK19), which are proposed as predictive markers of HCC cells disseminated into the circulation and for metastatic recurrence. Another important aspect is to analyze the molecular markers for cellular malignancy phenotype, including DNA ploidy, cellular proliferation index, cell cycle regulators, oncogenes, and tumor suppressors (especially p53 gene), as well as telomerase activity. Molecular factors involved in the process of HCC invasion and metastasis, including adhesion molecules (E-cadherin, catenins, ICAM-1, laminin-5, CD44 variants, osteopontin), proteinases responsible for the degradation of extracellular matrix (MMPs, uPA system), as well as angiogenesis regulators (such as VEGF, intratumor MVD), have also been shown to be potential predictors for HCC metastatic recurrence and clinical outcomes. One important new trend is to widely delineate biomarkers with genomic and proteomic expression with reference to predicting metastatic recurrence, molecular diagnosis, and classification, which has been drawing more attention recently. Body fluid (particularly blood and urine) testing for biomarkers is easily accessible and more useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum and its genetic alterations is another important direction. More attention should be paid to these areas in the future. As understanding of tumor biology deepens, more and more new biomarkers with high sensitivity and specificity for HCC metastatic recurrence could be found and routinely used in clinical assays. However, the combination of the pathological features and some of the biomarkers mentioned above seems to be more practical up to now.

Angiogenesis Inducing Agents↗
PubMed2001

A highly aggressive primitive mesenchymal tumor with a translocation (1;19)(q12;q13.2).

Soft tissue sarcomas constitute a heterogeneous group of malignant tumors of mesenchymal origin, the classification of which may present a diagnostic challenge. We present here the cytological, histopathological, immunohistochemical, and cytogenetic findings of an unusual case of a highly aggressive sarcoma. Based on the morphology and the immunohistochemical profile, this primitive tumor and its metastases could not be conclusively classified as any of the defined subtypes of sarcomas, although the findings were suggestive of a variant of rhabdomyosarcoma. Cytogenetic characterization using G-banding, SKY, FISH, and CGH revealed almost identical chromosomal compositions of the primary tumor and the metastasis. The hypertetraploid karyotype was characterized by numerical imbalances as well as by an unbalanced translocation t(1;19)(q12;q13.2), which has not been previously reported.

Amputation, Surgical↗
PubMed1997

Investigation of the CasCor Family of Learning Algorithms.

Six learning algorithms are investigated and compared empirically. All of them are based on variants of the candidate training idea of the Cascade Correlation method. The comparison was performed using 42 different datasets from the PROBEN1 benchmark collection. The results indicate: (1) for these problems it is slightly better not to cascade the hidden units; (2) error minimization candidate training is better than covariance maximization for regression problems but may be a little worse for classification problems; (3) for most learning tasks, considering validation set errors during the selection of the best candidate will not lead to improved networks, but for a few tasks it will. Copyright 1997 Elsevier Science Ltd.

Journal Article↗
PubMed2005

Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease.

BACKGROUND: The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrP(Sc)), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrP(Sc) display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively. METHODS: We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrP(Sc). FINDINGS: We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrP(Sc)-rich brain areas, with a typical PrP(Sc) type 1 migration pattern. INTERPRETATION: The regular coexistence of multiple PrP(Sc) types in patients with CJD casts doubts on the validity of electrophoretic PrP(Sc) mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.

Antibodies, Monoclonal↗
PubMed2002

Race, ethnicity, and genomics: social classifications as proxies of biological heterogeneity.

Over the past century, genetics has experienced a tension between the view that racial and ethnic categories are biologically meaningful and the view that these social classifications have little or no biological significance. That tension continues to inform genomics and is evident in the assembly of biological collections and sequence databases that seek to approximate the genetic variation found in human populations. Although social identities can be useful and convenient proxies of some biological features, for example, in ensuring that genomic resources capture a range of genetic variants found in most human populations, the ways in which geneticists conceptualize the relationship between racial and ethnic identities and genetic variation can be problematic. Inclusion of racial and ethnic identifiers in genomic resources can create risks for all members of those identified populations and influence lay perceptions of the nature of racial and ethnic groups. Thus, the burden of showing the scientific utility of racial and ethic identities in the construction and analysis of genomic resources falls on researchers. This requires that genetic researchers pay as much attention to the social constitution of human populations as presently is paid to their genetic composition.

Ethnicity↗
PubMed1998

[Differentiation and characterization of yeasts pathogenic for humans (Candida albicans, Exophiala dermatitidis) and algae pathogenic for animals (Prototheca spp.) using Fourier transform infrared spectroscopy (FTIR) in comparison with conventional methods].

Due to the Fourier-Transform Infrared Spectroscopy (FT-IR) of strain specific traits demonstrated to be a suitable and efficient method for diagnostic and epidemiological determinations for the yeasts Candida albicans, Exophiala dermatitidis and the chlorophylless algae of the genus Prototheca. FT-IR leads in a rapid and economical way to reproducible results according to the spectral differences of intact cells (IR-fingerprints). Different genera, species and sub-species respectively, different strains can be recognized and grouped into different clusters and subclusters. The FT-IR analysis of Candida albicans isolates (n = 150) of 22 newborns-at-risk of an intensive care unit showed, that 86% of the children were colonised with several (2-4) different strains in the oral cavities and faeces. Stationary cross-infections could definitely be determined. Exophiala dermatitidis isolates (n = 31), mostly isolated repetitively within a period of 3 years from sputa of patients suffering from cystic fibrosis could be characterized and grouped patient-specifically over the total sampling period. Of 6 from 8 patients (75%) their individual strains remain the same and could be tracked over the three years. Cross-infections during the stationary treatment could be clearly identified by FT-IR. The Prototheca isolate (n = 43) from live-stock and farm environment showed clear distinguishable clusters differentiating the species P. wickerhamii, P. zopfii and P. stagnora. In addition, the biotypes of P. zopfii could be distinguished, especially the subclusters of variants II and III. It could be demonstrated, that FT-IR is suitable for the routine identification and differentiation of yeasts and algae. However, in spite of the gain of knowledge by using FT-IR for the characterization of microorganisms, the conventional phenotyping and/or genetic analysis of yeast or algae strains cannot be replaced completely. For a final taxonomic classification a combination of conventional methods on FT-IR together with more sophisticated molecular genetic procedures is necessary.

Animals↗
PubMed1981

[Species makeup of coagulase-negative staphylococci of clinical origin].

The classification of Kloos--Schleifer was used for the identification of 175 clinical strains of coagulase-negative staphylococci. The species of staphylococci in 50.3% of the cultures were determined; as a result, S. epidermidis and S. saprophyticus were not found to be in the majority among them. The authors concluded that the above-mentioned scheme, as well as its short variant proposed by the International Subcommittee on the Taxonomy of Staphylococci and Micrococci could not be recommended for practical use.

Coagulase↗
PubMed1997

[Specific strategies in the treatment of young and middle-age patients with spontaneous intracerebral hemorrhage].

The paper is based on the analysis of 235 young and middle-age patients with non-traumatic cerebral hemorrhage. Tactics of treatment is determined for each group depending on bleeding localization in accordance with World Health Organization's classification (1981). Operative treatment is recommended for lateral site of hematomas of 25 cm3 and more signs of media structures dislocation of 5 mm and more. With the development of hypertension-hydrocephal syndrome surgical intervention is directed at its elimination and where possible at hematoma's ablation. The amount of operative interventions is limited in case of medial and mixed variants of hemorrhages especially when bleedings affect mesencephal structures. In conditions of a neurosurgical clinic a pharmacotherapy is used as an independent one, as a preparation for surgical treatment as well as during operation and in postoperative period.

Adult↗
PubMed1976

The isolation and some biological properties of a variant avian infectious bronchitis virus.

A virus isolated from a respiratory disease in chickens was identified as infectious bronchitis virus (IBV). By serum neutralisation tests the virus was shown to be serologically distinct from the Massachusetts type but to possess a one-way relationship with the Connecticut type. Experimentally, it caused a relatively mild respiratory disease in baby chicks. Vaccination of young chicks with H-120 Massachusetts IBV vaccine afforded a high degree of protection against challenge with the isolate. Some problems relating to the isolation and classification of field strains of IBV are briefly discussed.

Animals↗
PubMed2006

Whole genome association mapping by incompatibilities and local perfect phylogenies.

BACKGROUND: With current technology, vast amounts of data can be cheaply and efficiently produced in association studies, and to prevent data analysis to become the bottleneck of studies, fast and efficient analysis methods that scale to such data set sizes must be developed. RESULTS: We present a fast method for accurate localisation of disease causing variants in high density case-control association mapping experiments with large numbers of cases and controls. The method searches for significant clustering of case chromosomes in the "perfect" phylogenetic tree defined by the largest region around each marker that is compatible with a single phylogenetic tree. This perfect phylogenetic tree is treated as a decision tree for determining disease status, and scored by its accuracy as a decision tree. The rationale for this is that the perfect phylogeny near a disease affecting mutation should provide more information about the affected/unaffected classification than random trees. If regions of compatibility contain few markers, due to e.g. large marker spacing, the algorithm can allow the inclusion of incompatibility markers in order to enlarge the regions prior to estimating their phylogeny. Haplotype data and phased genotype data can be analysed. The power and efficiency of the method is investigated on 1) simulated genotype data under different models of disease determination 2) artificial data sets created from the HapMap ressource, and 3) data sets used for testing of other methods in order to compare with these. Our method has the same accuracy as single marker association (SMA) in the simplest case of a single disease causing mutation and a constant recombination rate. However, when it comes to more complex scenarios of mutation heterogeneity and more complex haplotype structure such as found in the HapMap data our method outperforms SMA as well as other fast, data mining approaches such as HapMiner and Haplotype Pattern Mining (HPM) despite being significantly faster. For unphased genotype data, an initial step of estimating the phase only slightly decreases the power of the method. The method was also found to accurately localise the known susceptibility variants in an empirical data set--the DeltaF508 mutation for cystic fibrosis--where the susceptibility variant is already known--and to find significant signals for association between the CYP2D6 gene and poor drug metabolism, although for this dataset the highest association score is about 60 kb from the CYP2D6 gene. CONCLUSION: Our method has been implemented in the Blossoc (BLOck aSSOCiation) software. Using Blossoc, genome wide chip-based surveys of 3 million SNPs in 1000 cases and 1000 controls can be analysed in less than two CPU hours.

Chromosome Mapping↗
PubMed1980

Spinal melanotic clear-cell sarcoma: a light and electron microscopic study.

We report a melanotic spindle-cell tumor that arose from a thoracic spinal nerve root and metastasized to both lungs. The bulk of the tumor consisted of glycogen-rich clear cells and bore a striking resemblance on light and electron microscopy to at least one variant of the clear-cell sarcoma of tendons and aponeuroses. The presence of schwannoma-like areas noted in the primary tumor on light microscopy and the formation of a highly developed basal lamina noted on ultrastructural examination suggest that the tumor may be a partially dedifferentiated malignant melanotic schwannoma. This tumor is discussed in the context of a simple histogenetic classification of melanotic tumors.

Adolescent↗