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PubMed1988

Hepatocellular carcinoma: importance of histologic classification as a prognostic factor.

The characteristics and clinical courses of 15 patients with fibrolamellar carcinoma have been compared to 62 patients with hepatocellular carcinoma treated over the same time period. Marked differences were found in patient, tumor, and treatment characteristics. Survival rates in these two groups of patients have been compared by univariate analysis of the subsets of those patient, tumor, and treatment characteristics. The longer survival of the group of patients with fibrolamellar carcinoma could not be accounted for by the prevalence or absence of any of these characteristics. Comparison of subsets of patients with documented noncirrhotic livers or those having complete resection of their tumors revealed a significantly prolonged survival in patients with the fibrolamellar variant. The 5 year survival rate of the patients with fibrolamellar carcinoma who had complete tumor resection was 45 percent, with a median survival time of 50 months. The 5 year survival of patients with hepatocellular carcinoma who had complete tumor resection was 0 percent, with a median survival time of 22 months.

Adolescent↗
PubMed2002

Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.

OBJECTIVE: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively. METHODS: Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA). RESULTS: Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA. CONCLUSION: These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Adult↗
PubMed1991

Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine.

The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by XbaI 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.

Adolescent↗
PubMed2006

Large-scale data exploration with the hierarchically growing hyperbolic SOM.

We introduce the Hierarchically Growing Hyperbolic Self-Organizing Map (H2SOM) featuring two extensions of the HSOM (hyperbolic SOM): (i) a hierarchically growing variant that allows for incremental training with an automated adaptation of lattice size to achieve a prescribed quantization error and (ii) an approximate best match search that utilizes the special structure of the hyperbolic lattice to achieve a tremendous speed-up for large map sizes. Using the MNIST and the Reuters-21578 database as benchmark datasets, we show that the H2SOM yields a highly efficient visualization algorithm that combines the virtues of the SOM with extremely rapid training and low quantization and classification errors.

Algorithms↗
PubMed2002

Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors.

BACKGROUND: In 1999, the World Health Organization (WHO) categorized large cell carcinoma with neuroendocrine features as variants of large cell carcinoma and reclassified neuroendocrine lung tumors, especially typical and atypical carcinoid tumors. However, to date, the clinical relationship between these categories of neuroendocrine lung tumors has not been clearly defined. METHODS: We analyzed 133 cases of neuroendocrine tumors from primary lung carcinoma cases surgically resected. Using electron microscopy and immunohistochemical staining, we classified these cases as typical carcinoid (TC), atypical carcinoid (AC), large cell carcinoma with neuroendocrine features (LCNF), or small cell lung carcinoma (SCLC) based upon the WHO classification. RESULTS: TC and AC tumors were not related to smoking (p < 0.001) and, unlike LCNF, were found in younger patients (p < 0.001) without a male predominance (p < 0.001). Multivariate analysis revealed that LCNF predicted poorer overall and disease-free survivals comparable with SCLC (overall survival, p = 0.019, hazards ratio, 6.34; disease-free survival, p = 0.007, hazards ratio, 8.19). CONCLUSIONS: The prognoses of LCNF are comparable with those of SCLC, and LCNF should be classified as high-grade neuroendocrine tumors.

Adolescent↗
PubMed1979

Clinical applications of the enzyme labeled antibody method. Immunoperoxidase methods in diagnostic histopathology.

Histological criteria for the definition of disease entities have largely been established with light microscopy of conventionally stained and routinely processed tissue sections. More or less specific histochemical staining procedures and more recently enzyme-histochemical and quantitative histo- and cytochemical techniques in some cases provided additional criteria. In the last decade, however, the introduction of immunofluorescence and more recently the different immunoperoxidase methods have significantly influenced the scope of contemporary histopathology. Especially, the possibility to use immunoperoxidase methods on routinely processed tissue specimens has offered new dimensions in diagnostic pathology. These methods proved of particular importance for: 1) The development of new criteria for diagnosis, prognosis and treatment (e.g. immunological classification of lymphoma; plasmacell typing in intestinal inflammatory conditions; human chorionic gonadotropin and alpha-fetoprotein in germ cell tumors of the testis). 2) The possibility of etiological diagnosis (e.g. the recognition of hepatitis B viral antigens in liver biopsy specimens; histological typing of causative micro-organisms in inflammatory conditions). 3) The recognition of disease entities that were hitherto unrecognized (e.g. hyperplasia of parafolicular C-cells in the thyroid in multiple endocrine neoplasia syndromes; gastric G-cell hyperplasia as a variant of Zollinger-Ellisons syndrome). 4) Functional analysis of tissue components (e.g. hormone content of pituitary and pancreatic adenomas; cytoplasmic differentiation produces in "undifferentiated" tumors). It can be expected that immunoenzymehistochemistry will soon play a major role in routine diagnostic histopathology.

Antigen-Antibody Reactions↗
PubMed1990

Bovine virus diarrhoea virus: an introduction.

In view of the recently established genome organisation of pestiviruses, their classification as members of the togavirus family is no longer tenable. They should rather be provisionally considered as a new genus of the Flaviviridae, irrespective of differences in the nonstructural genes. Like other positive-stranded RNA viruses, pestiviruses are highly variable; apart from point mutations, recombinations are expected to contribute to their capricious behaviour. One trait of expected pathogenetic significance in infections with bovine virus diarrhoea virus is a change from the non-cytopathogenic to a cytopathogenic biotype. Cooperation of both variants in an animal to produce the severe disease picture known as mucosal disease is unique in virology; elucidation of this mechanism may shed light on the pathogenesis of other sporadic diseases with suspected viral origin.

Animals↗
PubMed1980

[Mechanism and means of eliminating induced luminescence in immunofluorescence].

The causes of the appearance of induced fluorescence are discussed. The classification of its different forms is proposed. A hypothesis on the role of cytophilic properties of fluorescent antibodies in the mechanism of induced nonspecific fluorescence is put forward. This hypothesis has been experimentally confirmed in the studies in the field of obtaining the Fab fragments of fluorescent antibodies and their approbation. Conclusion has been made concerning the good prospects and advisability of using the Fab fragments of antibodies as an immunofluorescent reagent; the Fab fragments of pure antibodies may be considered an ideal variant of such a reagent.

Fluorescent Antibody Technique↗
PubMed1986

Cytokeratins of the bovine hoof: classification and studies on expression.

The bovine hoof has been examined as a model for the study of keratinized skin appendages. We characterized the keratin polypeptides of hoof bed and matrix and compared them to epidermis using two-dimensional electrophoresis and immunoblot techniques. Both hoof tissues express keratins 6 and 16 (as described by Franke et al. (1981) J. Mol. Biol. 153, 933-959) and b2 and a1-4 which are previously undescribed proteins unique to the bovine hoof. Keratins of hoof matrix and bed share one or more common antigenic components as defined by immunoblot analysis. Hoof matrix expresses keratins 7 and 14, which are absent in hoof bed, and also expresses a greater number of isoelectric variants of keratin 6. Biopsies of hoof bed and matrix transplanted onto athymic mice both made hard hoof and underwent active keratin synthesis as evidenced by incorporation of [3H]leucine. Indirect immunofluorescence studies of the grafts showed that they had the histology and immunoreactivity previously noted for hoof bed and matrix. The two-dimensional gel electrophoretic patterns of both grafts were similar and expressed keratins b2 and a1-4. We conclude that a unique group of keratins exists in hoof. Furthermore, while hoof matrix is the major contributor to hard hoof, hoof bed epidermis maintains the capacity to make hard hoof and may contribute to the synthesis of the hoof plate in vivo. The ability to graft hoofs onto athymic mice provides an opportunity for the study of a number of aspects of hoof formation.

Animals↗
PubMed2003

Analysis of skin line pattern for lesion classification.

BACKGROUND/PURPOSE: It has been observed that skin patterning tends to be disrupted by malignant but not by benign skin lesions. This suggests that measurements of skin pattern disruption on simply captured white light optical skin images could be a useful contribution to a diagnostic feature set. Previous work using a measurement of line strength by a consistent high-value profiling technique followed by local variance measurement or a region agglomerative classifier to measure skin line pattern disruption was extremely promising but computationally intensive, suggesting that the idea of measuring skin pattern disruption was useful but a simpler method was required. METHODS: The skin pattern was extracted by high-pass filtration and enhanced by adaptive anisotropic (spatial variant) filtering which smoothes along skin lines but not across them. The skin line main direction and direction variance were estimated using a local image gradient matrix and the difference of these measures across the lesion image boundary was used as a lesion classifier. RESULTS: A set of images of malignant melanoma and benign naevi were processed as above and the scatter plot of results in a two-dimensional feature (line direction and line variation difference) space showed excellent separation of benign and malignant lesions. An ROC plot enclosed an area of 0.88. CONCLUSIONS: The experimental results showed that the local line direction and the local line variation were promising features for distinguishing malignant melanoma from benign lesion and the methods used were effective and computationally low-cost.

Algorithms↗
PubMed1996

Glycophorin A somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene.

We have used the glycophorin A (GPA) in vivo somatic cell mutation assay to assess the genotoxic potential of styrene exposure in 47 reinforced plastics workers occupationally exposed to styrene and 47 unexposed controls matched for age, gender, and active smoking status. GPA variant erythrocyte frequencies (Vf), reflecting GPA allele loss (phi/N) and allele loss and duplication (N/N) somatic mutations arising in vivo in the erythroid progenitor cells of individuals of GPA M/N heterozygous genotype, were flow cytometrically determined in peripheral blood samples from these subjects. Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA8-h) styrene concentration of 155 mg/m3 (37 ppm) in the breathing zone. Mean urinary concentrations of the styrene metabolites mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA+PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next morning), respectively. Multivariate analysis of covariance on log-transformed GPA Vf data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N Vf were nearly significantly increased among all of the exposed workers (adjusted geometric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6.8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA8-h concentration of styrene in the breathing zone of > or = 85 mg/m3 (20 ppm; Finnish threshold limit value). Women in this high exposure group showed especially elevated N/N Vf (adjusted geometric mean 8.5 versus 5.3 in control women; P = 0.020); this elevation was also significant if urinary MA+PGA of > or = 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030). The occupational exposure could not be shown to influence phi/N Vf. Cigarette smoking was associated with significantly elevated GPA Vf among active smokers (P = 0.042 for phi/N and P = 0.020 for N/N) and among active and ex-smokers combined (P = 0.014 for N/N). Its influence on phi/N Vf was especially clear among active smokers in the control group (P = 0.005). An effect of smoking, nearly statistically significant, was also observed for the phi/N Vf of control ex-smokers (P = 0.055) and of all active and ex-smokers combined (P = 0.050). Thus, the two characterized chemical exposures experienced by this group of workers and controls appear to produce differential effects on the two independent classes of GPA variants enumerated in the assay. This result suggests that the genotoxicity of these agents is mediated, at least in part, by different genetic mechanisms. Styrene exposure is associated with a specific increase in GPA N/N Vf; these allele loss and duplication variants reflect predominantly somatic recombination mechanisms in erythroid progenitor cells. Tobacco smoke exposure in active and ex-smokers is also associated not only with an increase in N/N Vf but also with an increase in phi/N Vf, reflecting the induction of GPA gene-inactivating mutations, including point mutations and deletions. This finding is consistent with a broad mechanistic spectrum of tobacco smoke genotoxicity associated with this complex mixture of chemical mutagens. Finally, there was no detectable effect of age on phi/N Vf; however, a highly significant (P = 0.0002) increase in N/N Vf with age, even after adjustment for other variables, was observed.

Adult↗
PubMed2001

Genetic relatedness of Cuban HAV wild-type isolates.

Knowledge of the nucleotide sequence in the region of the putative VP1/2A junction of the Hepatitis A virus (HAV) genome has enabled differentiation of HAV strains and their classification into seven genotypes, in some of which sub-genotypes A and B can be defined. A 168 base segment encompassing the putative VP1/2A junction of 27 clinical wild-type isolates of HAV from Cuba was amplified by reverse transcriptase-polymerase chain reaction and then sequenced. The Cuban isolates are clustered within sub-genotype IA. A single amino acid substitution, which does not correspond with any of the reported changes for other strains, was observed. A new sub-genotype variant is therefore postulated. This study provides new data on the genetic relatedness of HAVs from Cuba and on the distribution of sub-genotype IA in the Caribbean area.

Adult↗
PubMed2026

Next-generation sequencing in head and neck sarcoma: a single-centre institutional experience and review of the literature.

Head and neck sarcomas (HNS) are rare, heterogeneous malignancies representing less than 1% of head and neck cancers. Their complex anatomy and overlapping morphologies pose significant challenges for traditional diagnosis. We aimed to evaluate the clinical utility of next-generation sequencing (NGS) within a tertiary referral centre and synthesise these findings with current global molecular standards. We conducted a retrospective review of an original, previously unpublished, cohort of 12 patients with histologically verified HNS treated at University College London Hospital (UCLH) between 2023 and 2024. Molecular profiling included targeted DNA (RMH200) and RNA-fusion panels. This was supplemented by a qualitative synthesis of 16 key studies (2010-2026) identified through a systematic search strategy. In the institutional cohort, NGS provided definitive diagnostic or therapeutic clarification in 66% of cases (8/12). Key findings included the identification of pathognomonic fusions (such as EWSR1::FLI1, PAX3::MAML3), a novel MAMLD1::VGLL3 fusion, and actionable variants such as BRAF V600E and MYOD1. Furthermore, the formal exclusion of Neurotrophic tropomyosin receptor kinase (NTRK) fusions in some cases allowed for therapeutic streamlining. Literature synthesis aligned these results and emphasised the need for NGS for more accurate diagnosis and adequate treatment. NGS is a clinical necessity in the management of ultra-rare HNS. By transitioning from traditional morphology to high-resolution molecular interrogation, clinicians can resolve diagnostic ambiguity and identify targeted therapeutic pathways. Integration with emerging 2026 standards, including epigenetic classification and liquid biopsy monitoring, represents the future of precision surgery in head and neck sarcoma.

Humans↗
PubMed2001

Characterization of ATI, TK and IFN-alpha/betaR genes in the genome of the BeAn 58058 virus, a naturally attenuated wild Orthopoxvirus.

The lack of knowledge about the natural host of Vaccinia virus (VV) along with the description of human infections caused by poxviruses after smallpox eradication has increased the need to characterize poxviruses isolated from the wild. Moreover, in the past years poxviruses have been widely studied as potential vaccination tools, with the discovery of several genes implicated in the evasion of the host immune response involved in virus pathogenesis. Among them, an Interferon (IFN)-binding protein was identified in the supernatant of VV strain WR infected cells coded by the B18R gene. It was shown that many other Orthopoxviruses also encode and express this soluble receptor although some VV strains such as Lister and modified Ankara, which were less reactogenic vaccines, do not. The BeAn 58058 virus (BAV) has been recently characterized and proposed to be an Orthopoxvirus. BAV was also shown to be less virulent in animal models than VV Lister. Here we report the identification of an IFN-alpha/betaR gene in the BAV genome with 99% of sequence identity with the VVWR B18R gene. The identified gene encodes a B18R-like IFN binding protein as demonstrated by its capacity to inhibit the IFN-mediated protection of VERO cells against EMC virus. In order to better characterize the virus we have searched for the A type inclusion body (ATI) gene currently used in the classification of Orthopoxviruses but did not detect it in the BAV genome. We have also sequenced the BAV thymidine kinase (TK) gene, a poxvirus-conserved gene, which, as expected, showed high homology with the TK gene of other poxviruses. Phylogenetic trees were constructed based on sequences of the IFN-alpha/betaR and TK genes from several poxviruses and in both cases BAV was placed in the same cluster as other VV strains. These observations strengthened the hypothesis that this virus is a variant of the VV vaccine used in Brazil. However the explanation for the BAV lack of virulence remains to be discovered.

Amino Acid Sequence↗
PubMed1995

An unusual form of localized papulonodular cutaneous histiocytosis in a 6-month-old boy.

We report a 6-month-old boy with an unusual form of cutaneous histiocytosis. The lesions were noticed shortly after birth, and there was no evidence of systemic disease. This histiocytic disorder could not be classified according to the Histiocyte Society classification, and was therefore designated an 'unclassified' group II histiocytic disorder. The clinical picture was characterized by dark-red papulonodules with a tendency to coalesce into plaques. Histologically, the infiltrate was characterized by non-epidermotropic histiocytes showing varying degrees of differentiation, eosinophils and lymphocytes, and by the absence of foamy cells and Touton giant cells. As a most conspicuous feature, electron microscopic examination revealed laminated dense bodies, whereas Birbeck granules and comma-shaped bodies were absent. This further distinguished this uncommon variant from the well-known class II histiocytoses. During a 6-month follow-up period all the lesions showed marked regression.

Anti-Inflammatory Agents↗
PubMed2006

Expression of novel molecules, MICAL2-PV (MICAL2 prostate cancer variants), increases with high Gleason score and prostate cancer progression.

PURPOSE: The aim of this study is to identify novel molecular targets for development of novel treatment or diagnostic markers of prostate cancer through genome-wide cDNA microarray analysis of prostate cancer cells purified by laser microdissection. EXPERIMENTAL DESIGN AND RESULTS: Here, we identified molecule interacting with CasL-2 prostate cancer variants (MICAL2-PV), novel splicing variants of MICAL2, showing overexpression in prostate cancer cells. Immunohistochemical analysis using an antibody generated specific to MICAL2-PV revealed that MICAL2-PV was expressed in the cytoplasm of cancer cells with various staining patterns and intensities, whereas it was not or hardly detectable in adjacent normal prostate epithelium or prostatic intraepithelial neoplasia. Interestingly, immunohistochemical analysis of 105 prostate cancer specimens on the tissue microarray indicated that MICAL2-PV expression status was strongly correlated with Gleason scores (P < 0.0001) or tumor classification (P < 0.0001). Furthermore, the expression levels of MICAL2-PVs were also concordant to those of c-Met, a marker of tumor progression, with statistical significance (P = 0.0018). To investigate its potential of molecular therapeutic target for prostate cancers, we knocked down endogenous MICAL2-PVs in prostate cancer cells by small interfering RNA, which resulted in the significant reduction of prostate cancer cell viability. CONCLUSIONS: Our findings suggest that MICAL2-PV is likely to be involved in cancer progression of prostate cancer and could be a candidate as a novel molecular marker and/or target for treatment of prostate cancers with high Gleason score.

Adaptor Proteins, Signal Transducing↗
PubMed1988

[Immunohistologic findings in paragangliomas in the area of the head and neck].

30 patients with paraganglioma of the head and neck region were subjected to surgery at the Department of Otorhinolaryngology during 1978-1985. Histological classification of the obtained specimens was performed using also immunocytochemical methods to detect more details. The site of origin of the tumours was the glomus tympanicum in 18 cases, 7 times the glomus caroticum and 5 times the glomus jugulare. Antibodies against neuronal components (S-100 protein), endothelial cells (UEAI) and endocrine activity (NSE) were used for subtyping by PAP-method (Figs. 1-3). Immunocytochemistry provided for an easy subtyping of the tumours and showed an increase in severe progress forms in adenomatous variants of paragangliomas.

Adult↗
PubMed1985

A serological classification of bovine enteroviruses.

Cross virus neutralization (VN), complement fixation (CF) and immunoprecipitation (IP) tests were employed to compare the seven currently recognized bovine enterovirus (BEV) serotypes with seven serologically distinct strains previously isolated in Great Britain and two other BEV from the United Kingdom. Based on criteria used to differentiate other human and animal picornavirus serotypes, it was discovered that BEV types 1, 4, 5 and 6 were related to each other and could be included in a single serotype. Types 3 and 7 were found to be identical, and related to serotype 2. All of the other nine BEV were included in either serotype 1 or 2. Not all of the strains in each serotype were identical and antigenic variants were designated as subtypes. Antigenic relationships not revealed by VN were demonstrated in CF and IP tests. Bovine enterovirus strains whose antisera had the broadest intratypic reactivity were suggested as prototypes. The two proposed BEV serotypes could also be distinguished by their ability to agglutinate erythrocytes. Guinea pig erythrocytes were agglutinates by both serotypes while sheep red cells only reacted with serotype 1.

Animals↗