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At least 523 records · Page 29Linked to original sources
PubMed2002

Are there two sides to colorectal cancer?

Colorectal carcinomas (CRC) that arise proximal (right) or distal (left) to the splenic flexure exhibit differences in incidence according to geographic region, age and gender. Together with observations that tumours in the hereditary cancer syndromes HNPCC and FAP occur predominantly in the right and left colon, respectively, the existence of 2 categories of CRC based on site of origin in the large bowel was proposed more than a decade ago. Differences between normal right and left colonic segments that could favour progression through different tumourigenic pathways are summarized in this review. Accumulating evidence suggests that the risk of CRC conferred by various environmental and genetic factors is different for proximal and distal tumours. Right- and left-sided tumours also exhibit different sensitivities to fluorouracil-based chemotherapy. Such differences are probably related to the molecular characteristics of the tumours, with the microsatellite instability and CpG island methylator phenotypes being associated with right-sided tumours and chromosomal instability with left-sided tumours. Future molecular-based classification systems for CRC that rely upon distinctive gene expression patterns may allow a clearer discrimination of subgroups than that provided by tumour site alone. Until then however, the existence of 2 broadly different groups of cancer defined by site of origin in the colon should be considered in the design of future epidemiologic studies as well as in the design of new clinical trials aimed at testing novel adjuvant therapies.

Colonic Neoplasms↗
PubMedDate not supplied

Suprageneric classification of peptidoglycan group B actinomycetes by nucleotide sequencing of 5S ribosomal RNA.

5S ribosomal RNA sequences were determined for thirteen actinomycetes mainly representatives with the rare group B type peptidoglycan. The primary and secondary structure of the resultant sequences were of the type characteristic of Gram-positive bacteria with DNA rich in guanine plus cytosine. The sequencing and associated chemotaxonomic data provide compelling grounds for classifying actinomycetes with a group B type peptidoglycan in a single family. The family Microbacteriaceae fam. nov. is proposed to accommodate actinomycetes classified in the genera Agromyces, Aureobacterium, Clavibacter, Curtobacterium and Microbacterium.

Actinomyces↗
PubMed1994

Aspartate aminotransferase-linked immunoglobulin complexes in serum of a patient with primary biliary cirrhosis.

A 51-year-old woman who had been treated for primary biliary cirrhosis (PBC) was admitted to our hospital for evaluation of unexplained, isolated, persistently increased aspartate aminotransferase (AST) activity. Results of laboratory tests on admission showed: AST 171 KU, alanine aminotransferase 28 KU, and anti-mitochondrial titer 1/1280. Results of hepatitis B surface antigen (HBs Ag) and hepatitis C virus antibody (HCV Ab; C100-3) assays were negative. Histology of a liver biopsy specimen was compatible with a diagnosis of PBC (stage III of Scheuer's classification). The molecular size of serum AST was estimated to be more than 500,000 by high-performance size-exclusion liquid chromatography. Electrophoretic analysis showed an abnormal band of AST between supernatant AST (sAST) and mitochondrial AST (mAST), which band was characteristic of AST-immunoglobulin complexes (AST-Ig). Ouchterlony double-diffusion and immunoprecipitation tests identified the immunoglobulin component as IgM. The presence of AST-Ig appeared to be responsible for the elevated serum AST.

Aspartate Aminotransferases↗
PubMed1999

Focal and Diffuse Beta Cell Changes in Persistent Hyperinsulinemic Hypoglycemia of Infancy.

In recent years our understanding of the changes in the endocrine pancreas in persistent hyperinsulinemic hypoglycemia in infancy, a form of congenital hypoglycemia, has increased considerably, in terms of both morphological classification and molecular pathogenesis. This review summarizes the current state of knowledge about the pathological lesions in the pancreas and their relationship to recently reported molecular findings.

Journal Article↗
PubMed2006

Genomic screening of head and neck cancer and its implications for therapy planning.

Despite great technical improvements in radiotherapy and surgery, survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has still not improved significantly over the last decades. Management of SCCHN has mainly been based on the TNM staging and site over this time period, even though we know that there are individual differences independent of the TNM status. Individual patients with small tumors might have a poor outcome, and patients with large tumors may end up with a favorable prognosis, despite their respective TNM classification. Recent molecular studies indicate that underlying genetic abnormalities may reflect such individual differences independently of TNM status. Individualization of treatment based on such biological properties of the tumors might result in less over as well as under treatment. However, the optimal panel of biomarkers to be used for the individualization of treatment is yet to be defined. A variety of laboratory techniques have been used in studies that investigate the individual biological features, spanning from methods that screen the genome for chromosomal and genetic abnormalities, e.g., cytogenetics, CGH, SKY and cDNA micro array, to detailed studies of specific aberrations. The purpose of this review of the literature is to summarize what has been studied so far by methods for genetic screening and to relate these results to the prediction of the clinical outcome. We conclude that it is time to focus future prospective studies on how treatment can be individualized based on biomarkers in combination with the macroscopic features of SCCHN.

Biomarkers, Tumor↗
PubMed1990

The detection of genetic variation in Leptospira interrogans serogroup ICTEROHAEMORRHAGIAE by ribosomal RNA gene restriction fragment patterns.

Deoxyribonucleic acid from Leptospira interrogans serogroup ICTEROHAEMORRHAGIAE reference strains together with clinical and animal isolates were cleaved with EcoRI, electrophoresed and transferred to nylon membranes. An Escherichia coli MRE 600, 16S + 23S ribosomal RNA template was used in the synthesis of a single strand biotin-labelled cDNA probe using a reverse transcriptase. Ribosomal RNA cistrons present in the DNA fragments of strains were located using the cDNA probe. Between 4 and 7 well defined ribosomal RNA restriction bands were detected for the leptospires studied that varied in size from 12.1 to 0.57 kb. The hybridisation patterns were distinctive and unique for the reference strains that allowed for their characterisation. Similar patterns were observed for I. budapest M 20, I. "icterohaemorrhagiae" Ictero I and the type strain, I. icterohaemorrhagiae RGA. Clinical isolates and a isolate from a rat were compared with reference strain DNA patterns and identified as being similar to I. copenhageni M 20, I. "icterohaemorrhagiae" Ictero I and I. icterohaemorrhagiae RGA. These results indicate that ribosomal DNA fingerprinting may be useful in the classification and molecular epidemiology of pathogenic leptospires.

DNA Probes↗
PubMed2004

The effects of temperature reduction on gene expression and oxidative stress in skeletal muscle from adult zebrafish.

Longevity is inversely proportional to ambient temperature in ectothermic organisms such as fish. However, the mechanism by which reducing temperature over a physiological range increases life span is not known and available data are derived primarily from invertebrates. With a rodent-like longevity and abundant biological resources, the zebrafish is an ideal vertebrate ectothermic model in which to investigate this phenomenon. As an initial approach, the effects of a year-long 10 degrees C reduction in water temperature on global gene expression in tail skeletal muscle from adult zebrafish were determined using an oligonucleotide microarray representing 15,512 genes. Expression levels for approximately 600 genes were up-regulated by 1.7-fold or greater by the reduction in temperature, while a similar number of transcripts were down regulated by more than 1.7-fold. Using gene ontology (GO) classifications for molecular function, two functional groups, "oxygen and reactive oxygen species metabolism" and "response to oxidative stress," were found to be overrepresented among up-regulated genes. Transcripts levels for the genes in these two categories were increased by temperature reduction (TR). However, temperature reduction did not suppress lipid peroxidation potential, protein carbonyl content, or 8-oxoguanine level. Additional studies will be required to further delineate the role of altered gene expression and oxidative stress on the longevity-promoting effects of temperature reduction.

Aging↗
PubMed2006

The use of gene-expression profiling to better understand the clinical heterogeneity of estrogen receptor positive breast cancers and tamoxifen response.

In a short period of time DNA microarray technology has revolutionized our understanding of human cancer biology. This has been particularly impressive in the field of breast cancer research, where the clinical heterogeneity long observed by physicians seems to be mirrored by different molecular phenotypes exposed by microarray analysis. Gene-expression signatures have been developed to predict prognosis and treatment response and pending adequate validation, are on the verge of entry into the clinical setting. In this review article we explore how gene-expression profiling has influenced our understanding of the ER-positive breast cancers: that proliferation and cell-cycle genes seem to be the strongest predictor for metastasis and relapse in this group, and discuss the various gene predictors and molecular subtype classifications that exist that may help us individualize therapy for these women.

Biomarkers↗
PubMed2005

Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis.

Diagnosis of synchronous endometrioid carcinomas of the uterine corpus and ovary as either separate independent primary or as metastatic tumors requires careful consideration of a number of gross and histological features. Although such assessment is often sufficient, recent evidence has suggested that molecular analysis may facilitate the diagnosis in problematic cases. Furthermore, as independent synchronous tumors limited to the uterus and ovary are generally associated with favorable outcome, determination of genetic alterations associated with this group of neoplasms may indicate molecular markers of less aggressive behavior. We examined 12 cases of synchronous carcinomas of the uterus and ovary, correlating conventional gross and histological parameters with molecular genetic alterations common to single endometrioid carcinomas occurring in these sites. We identified a frequency of molecular alterations in both independent and metastatic tumors, including microsatellite instability (uterine tumors, 50% and 67%, respectively; ovarian tumors, 33% and 67%) and PTEN mutations (uterine tumors, 38% and 100%; ovarian tumors, 33% and 83%) that is higher than that observed in single sporadic tumors. Loss of heterozygosity for chromosome 17p and 10q was also frequently observed. Nuclear immunoreactivities for beta -catenin and CTNNB1 mutations were restricted to independent uterine and ovarian tumors and were absent in all of the metastatic tumors, providing direct evidence for a divergence of molecular oncogenetic mechanisms in the subset of synchronous endometrioid carcinomas. Furthermore, our data show that molecular genetic classification of synchronous independent versus metastatic tumors based on beta -catenin expression/mutation correlates with clinical outcome.

Adult↗
PubMed2026

Integrated expression profiling of trophoblast cell-surface antigen 2 (TROP2), folate receptor alpha (FRα), and human epidermal growth factor receptor 2 (HER2) in endometrial Cancer across molecular classes, genomic alterations, and histologic subtypes.

OBJECTIVE: Antibody-drug conjugates (ADCs) are expanding treatment options in endometrial carcinoma, but the distribution of actionable surface targets across histologic, molecular, and genomic subgroups remains incompletely defined. METHODS: This single-institution retrospective tissue microarray (TMA) study included 312 endometrial carcinomas: 158 endometrioid and 154 serous tumors. Trophoblast cell-surface antigen 2 (TROP2) was quantified by histochemical score (H-score); human epidermal growth factor receptor 2 (HER2) was assessed using endometrial carcinoma-specific and gastric/DESTINY-PanTumor02 criteria; and folate receptor alpha (FRα) positivity was defined as ≥75% viable tumor cells with ≥2+ membranous staining. Molecular class was assigned using a hierarchical DNA polymerase epsilon (POLE)-mutant, microsatellite instability/mismatch repair-deficient (MSI/MMRd), p53-abnormal, and no specific molecular profile (NSMP) classifier. Tumor mutational burden (TMB) and recurrent genomic alterations were analyzed in relation to biomarker expression. RESULTS: TROP2 was broadly expressed, with median H-scores of 280 in endometrioid and 200 in serous carcinomas. HER2 gastric-score 2+/3+ expression and FRα positivity were enriched in serous versus endometrioid carcinoma (22.5% vs 8.9% and 20.1% vs 4.4%), restricted to FIGO grade 3 tumors, and concentrated in p53-abnormal disease. FRα positivity was absent in POLE-mutant and MSI/MMRd tumors. HER2 2+/3+ expression correlated with erb-b2 receptor tyrosine kinase 2 (ERBB2) alterations, whereas FRα-positive tumors were enriched for TP53 alterations and showed lower frequencies of ARID1A and PTEN alterations. Triple-negative TROP2/HER2/FRα tumors were uncommon (6/308, 1.9%). CONCLUSIONS: TROP2 is broadly expressed in endometrial carcinoma, whereas HER2 and FRα define a more restricted high-grade, serous/serous-like, p53-abnormal compartment, supporting biomarker-informed ADC development.

Humans↗
PubMed2001

Expression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers.

The expression patterns of 7075 genes were analyzed in four conventional (clear cell) renal cell carcinomas (RCC), one chromophobe RCC, and two oncocytomas using cDNA microarrays. Expression profiles were compared among tumors using various clustering algorithms, thereby separating the tumors into two categories consistent with corresponding histopathological diagnoses. Specifically, conventional RCCs were distinguished from chromophobe RCC/oncocytomas based on large-scale gene expression patterns. Chromophobe RCC/oncocytomas displayed similar expression profiles, including genes involved with oxidative phosphorylation and genes expressed normally by distal nephron, consistent with the mitochondrion-rich morphology of these tumors and the theory that both lesions are related histogenetically to distal nephron epithelium. Conventional RCCs underexpressed mitochondrial and distal nephron genes, and were further distinguished from chromophobe RCC/oncocytomas by overexpression of vimentin and class II major histocompatibility complex-related molecules. Novel, tumor-specific expression of four genes-vimentin, class II major histocompatibility complex-associated invariant chain (CD74), parvalbumin, and galectin-3-was confirmed in an independent tumor series by immunohistochemistry. Vimentin was a sensitive, specific marker for conventional RCCs, and parvalbumin was detected primarily in chromophobe RCC/oncocytomas. In conclusion, histopathological subtypes of renal epithelial neoplasia were characterized by distinct patterns of gene expression. Expression patterns were useful for identifying novel molecular markers with potential diagnostic utility.

Adult↗
PubMedDate not supplied

Reoptimization of MDL keys for use in drug discovery.

For a number of years MDL products have exposed both 166 bit and 960 bit keysets based on 2D descriptors. These keysets were originally constructed and optimized for substructure searching. We report on improvements in the performance of MDL keysets which are reoptimized for use in molecular similarity. Classification performance for a test data set of 957 compounds was increased from 0.65 for the 166 bit keyset and 0.67 for the 960 bit keyset to 0.71 for a surprisal S/N pruned keyset containing 208 bits and 0.71 for a genetic algorithm optimized keyset containing 548 bits. We present an overview of the underlying technology supporting the definition of descriptors and the encoding of these descriptors into keysets. This technology allows definition of descriptors as combinations of atom properties, bond properties, and atomic neighborhoods at various topological separations as well as supporting a number of custom descriptors. These descriptors can then be used to set one or more bits in a keyset. We constructed various keysets and optimized their performance in clustering bioactive substances. Performance was measured using methodology developed by Briem and Lessel. "Directed pruning" was carried out by eliminating bits from the keysets on the basis of random selection, values of the surprisal of the bit, or values of the surprisal S/N ratio of the bit. The random pruning experiment highlighted the insensitivity of keyset performance for keyset lengths of more than 1000 bits. Contrary to initial expectations, pruning on the basis of the surprisal values of the various bits resulted in keysets which underperformed those resulting from random pruning. In contrast, pruning on the basis of the surprisal S/N ratio was found to yield keysets which performed better than those resulting from random pruning. We also explored the use of genetic algorithms in the selection of optimal keysets. Once more the performance was only a weak function of keyset size, and the optimizations failed to identify a single globally optimal keyset. Instead multiple, equally optimal keysets could be produced which had relatively low overlap of the descriptors they encoded.

Algorithms↗
PubMedDate not supplied

The maximum common substructure as a molecular depiction in a supervised classification context: experiments in quantitative structure/biodegradability relationships.

The maximum common structure between two molecules (MCS) induces a similarity that enables one to group compounds sharing the same pattern. This text relates a study based on such a structural depiction in a context of quantitative structure/biodegradability relationships (QSBR). The similarity indices are based exclusively on the MCS. First, the results of statistical tests prove that these indices significantly group compounds of similar activity together. These first conclusions enable the elaboration of classification models using those structural similarities. In a second part, a population of classifiers relying on the maximum common structure and the k-nearest-neighbor algorithm is explored. Finally, a thorough examination of the best models is conducted.

Algorithms↗
PubMed1998

Plant O-methyltransferases: molecular analysis, common signature and classification.

Comparative analysis of the predicted amino acid sequences of a number of plant O-methyltransferase cDNA clones show that they share some 32-71% sequence identity, and can be grouped according to the different compounds they utilise as substrates. Five highly conserved regions are proposed as a signature for plant O-methyltransferases, two of which (regions I and IV) are believed to be involved in S-adenosyl-L-methionine and metal binding, respectively. The glycine-rich signature regions include a 36 amino acid domain which is located in the mid-terminal section of the carboxy terminus of most O-methyltransferase sequences. Cladistic analysis of the amino acid sequences suggests that plant O-methyltransferases may have arisen from common ancestral genes that were driven by different structural and/or functional requirements, and whose descendants segregated into different biochemical species. A comprehensive classification of plant O-methyltransferases is proposed following the guidelines of the Commission of Plant Gene Nomenclature.

Amino Acid Sequence↗
PubMed2000

Peptides with antimicrobial activity from four different families isolated from the skins of the North American frogs Rana luteiventris, Rana berlandieri and Rana pipiens.

The skins of frogs of the genus Rana synthesize a complex array of antimicrobial peptides that may be grouped into eight families on the basis of structural similarity. A total of 24 peptides with differential growth-inhibitory activity towards the Gram-positive bacterium Staphylococcus aureus, the Gram-negative bacterium Escherichia coli and the yeast Candida albicans were isolated from extracts of the skins of three closely related North American frogs, Rana luteiventris (spotted frog), Rana berlandieri (Rio Grande leopard frog) and Rana pipiens (Northern leopard frog). Structural characterization of the antimicrobial peptides demonstrated that they belonged to four of the known families: the brevinin-1 family, first identified in skin of the Asian frog Rana porosa brevipoda; the esculentin-2 family, first identified in the European frog Rana esculenta; the ranatuerin-2 family, first identified in the North American bullfrog Rana catesbeiana; and the temporin family, first identified in the European frog Rana temporaria. Peptides belonging to the brevinin-2, ranalexin, esculentin-1 and ranatuerin-1 families were not identified in the extracts. Despite the close phylogenetic relationship between the various species of Ranid frogs, the distribution and amino-acid sequences of the antimicrobial peptides produced by each species are highly variable and species-specific, suggesting that they may be valuable in taxonomic classification and molecular phylogenetic analysis.

Amino Acid Sequence↗