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At least 1,099 records · Page 61Linked to original sources
PubMed2000

Cystinuria at the turn of the millennium: clinical aspects and new molecular developments.

Cystinuria is caused by a defect in a transport molecule in the kidney and small intestine resulting in urinary excretion of cystine and the dibasic amino acids. Traditionally, three types have been recognized, but this classification correlates poorly with the findings of molecular analysis, and a new system is needed. Persons who are homozygous and heterozygous for non-Type I cystinuria can be distinguished by urinary amino acid excretion: the former secrete large amounts of cystine and all three dibasic amino acids, whereas the latter secrete more lysine and cystine than arginine and ornithine. The first gene found that is important in cystine transport is SLC3A1, located on chromosome 2p. More than 40 mutations have been identified, all associated with Type I cystinuria. The gene associated with non-Type I disease maps to chromosome 19, called SLC7A9, encodes a protein that apparently interacts with the product of the SLC3A1 gene. Almost 40 disease-associated mutations have been identified in SLC7A9, and there is some evidence that cystinuria in some patients reflects mutations in both genes. Mutations in other proteins with which the SLC3A1 and SLC7A9 products associated may be responsible for still other cases of cystinuria. Contemporary molecular knowledge has not offered any new treatment for the short term.

Amino Acid Transport Systems, Basic↗
PubMed2005

Adult acute lymphoblastic leukemia.

Much progress has been made in understanding the biology of and therapy for acute lymphoblastic leukemia (ALL). This progress has translated into the recognition of several subgroups of ALL and the institution of risk-adapted therapies. New therapies are emerging based on the definition of specific cytogenetic-molecular abnormalities. Changes in the pathologic classification of ALL have led to therapeutic consequences. Adaptation of successful treatment strategies in children with ALL has resulted in similar complete remission rates in adults. Prognosis has Improved especially in mature B-cell ALL and T-cell lineage ALL. However, regardless of ALL subgroup, long-term survival in adults is still inferior to that in children. Development of new drugs and agents tailored to subset-specific cytogenetic-molecular characteristics is vital to the therapeutic success in adult ALL.

Adult↗
PubMed2006

[WHO classification 2004: tumors of the kidneys].

New entities, confirmed either by cytogenetic findings or by new molecular markers, have been included in the WHO 2004 renal tumor classification. Moreover, imaging improvements provide a better radiologic description of tumors. In this article, we will discuss the WHO 2004 classification and focus on the new entities and their macroscopic appearance. We will especially insist on the following entities: multilocular clear cell renal carcinoma, Xp11 translocation carcinoma, low-grade mucinous tubular carcinoma, epithelioid angiomyolipoma, and benign mixed epithelial and stromal tumor. We also discuss the new concept of hybrid oncocytoma and chromophobe renal cell carcinoma, as well as the Birt-Hogg-Dube syndrome, which is associated with kidney tumors.

Humans↗
PubMed2026

Molecular clusters and precision medicine in pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. Over the past two decades, the genomic characterization of PPGLs has profoundly transformed their diagnosis, classification, risk stratification, and therapeutic management. Up to 40% of PPGLs harbor germline pathogenic variants, the highest proportion among human neoplasms, and somatic driver events are identified in a substantial fraction of the remaining cases. Integrative multi-omic studies have established three main molecular clusters: a pseudohypoxic cluster driven by Krebs-cycle alterations (SDHx, FH, MDH2, DLST) and HIF-2α pathway alterations (VHL, EPAS1, EGLN1/2); a kinase-signaling cluster driven by activation of RAS/MAPK and PI3K/AKT pathways (RET, NF1, HRAS, TMEM127, MAX); and a Wnt-signaling cluster characterized primarily by MAML3 fusions. This review summarizes progress in PPGL genomics, highlighting geographic and sex-related particularities. Using EPAS1/HIF-2α and RET as paradigmatic examples, we illustrate how diverse germline, somatic, mosaic, and fusion events converge on common core signaling hubs that can be therapeutically exploited with FDA-approved selective inhibitors for relevant targets (e.g. belzutifan for HIF-2α; selpercatinib and pralsetinib for RET). We further review the genomic determinants of metastatic risk (SDHB, ATRX, TERT, and MAML3 fusions), the immune microenvironment of metastatic disease, and emerging radionuclide theranostics, liquid biopsy biomarkers, and integrative multi-omic approaches that are reshaping precision medicine for PPGLs.

Humans↗
PubMed1993

Classification of a new member of the TBE flavivirus subgroup by its immunological, pathogenetic and molecular characteristics: identification of subgroup-specific pentapeptides.

The antigenic, pathogenic and molecular characteristics of Turkish sheep encephalitis (TSE) virus, strain TTE80, were compared with other members of the tick-borne encephalitis (TBE) virus complex. Monoclonal antibodies with defined specificity for the flavivirus envelope glycoprotein distinguished TSE virus from louping ill (LI), western or far eastern TBE, Langat and Powassan virus in indirect immunofluorescence, haemagglutination-inhibition and neutralization tests. On the other hand, TSE virus, which produces an LI-like disease in sheep, resembled LI virus in mouse neurovirulence tests. Molecular homology data of all the structural genes of TSE virus compared with other tick-borne flaviviruses demonstrated that TSE virus is a distinct member in the TBE virus subgroup. The data are consistent with the conclusion that TSE virus has evolved by a separate evolutionary pathway as compared with the close antigenic relatives, western European, far eastern TBE viruses and LI virus. By aligning the encoded amino acids in the viral envelope glycoprotein of mosquito- and tick-borne flaviviruses, we have also identified subgroup-specific pentapeptide motifs for the tick-borne encephalitis, Japanese encephalitis and dengue subgroup viruses of the genus Flavivirus. These pentapeptides have important implications for the evolution, classification and diagnosis of flaviviruses.

Amino Acid Sequence↗
PubMed2026

Methylation profiling in CNS tumor diagnostics: a single-centre real-world experience from Central Europe.

Genome-wide DNA methylation profiling has transformed neuro-oncology by providing an objective, machine learning-based taxonomy that mitigates interobserver variability and refines the histo-molecular criteria of the current WHO classification. We evaluate the real-world diagnostic performance and clinical utility of this modality in a prospective, consecutively accrued three-year cohort of 291 central nervous system (CNS) tumors across a mixed adult-pediatric population. Successful profiling was completed in 95.9% of cases. Using the Epignostix classifier, a high-confidence diagnostic match (calibrated score [CS]&#x2009;&#x2265;&#x2009;0.84) was achieved in 70.3% of analyzable samples, while 26.5% returned lower-confidence scores (&#x2265;&#x2009;0.3 to <&#x2009;0.84) and only 3.2% remained completely unclassifiable (CS&#x2009;<&#x2009;0.3). When integrated into a comprehensive diagnostic framework, methylation profiling provided clinically useful results in 81.1% of cases, establishing diagnoses in 70 cases submitted for molecular subclassification and resolving diagnostic uncertainty or prompting major revisions in 149 histologically challenging tumors. Within truly ambiguous lesions, integration of methylome data dictated tumor grade modifications in 38.8% of cases (upgrading in 29.4% and downgrading in 9.4%), shifting patient risk stratification. Crucially, over half (52.7%) of the lower-confidence cases yielded meaningful clinical integration when supported by histomorphology and ancillary genetic or immunohistochemical markers, demonstrating that rigid score cutoffs should not dictate assay failure. Discrepant or misleading classifications occurred in 1.9%. Updating bioinformatic pipelines from version 11b4 to 12.8 rescued multiple ambiguous entries, increasing overall clinical utility to 84.1%. These findings demonstrate that integrating computational epigenomics with classical neuropathology enhances diagnostic precision, while highlighting the ongoing need for careful clinical-pathological correlation.

Central nervous system tumors↗
PubMed1994

Viral respiratory diseases in children: classification, etiology, epidemiology, and risk factors.

The epidemiology, molecular structure, cell tropism, and pathophysiology of many human disease-causing viruses have been painstakingly and elegantly characterized during the past 50 years. Vaccines and antiviral drugs of varying efficacy were developed and tested. Despite the relegation of smallpox to a freezer chest and the progress in the control of measles and hepatitis B, the viruses that cause respiratory tract infections remain significant causes of illness and death in pediatric populations worldwide. This discussion surveys the virus groups that contain nearly 200 distinct viruses that cause sporadic and epidemic respiratory infections in children. The epidemiology of infection with the influenza A and B, parainfluenza, and respiratory syncytial viruses and adenoviruses and their impact on infants and children and the groups at highest risk for morbid outcomes are discussed.

Acute Disease↗
PubMed1990

Molecular biology and leukaemia diagnosis.

The diagnosis and classification of leukaemia started with simple morphological examination and now embraces use of special stains, cytochemistry and immunophenotyping. Genetic studies have progressed from karyotyping to detection of genetic changes within genes. The methods described in this chapter are still at an early stage of development and, so far, have provided relatively little in the way of an extension of available diagnostic information. Sometimes the methods provide extensions to existing techniques, for example by the detection of bcr rearrangements in patients who have CML or ALL but do not have a detectable Philadelphia chromosome. Another example is retrospective diagnosis of gene rearrangements using DNA from slide preparations. However, it should be noted that it has only very recently been shown that there is likely to be a causal relationship between the Ph chromosome and leukaemia. Daley et al (1990) induced CML in mice by bone marrow transplantation of cells infected with a retrovirus encoding P210bcr/abl and Heisterkamp et al (1990) produced mice transgenic for a BCR/ABL P190 DNA construct and showed that the progeny died of acute leukaemia (mostly ALL). We have not summarized studies of the incidence of activated oncogenes such as RAS in leukaemia and myelodysplasia. Such oncogenes appear to be involved in many tumours and may well indicate either a predisposition to cancer or a particular stage of malignancy, but their analysis does not at present help in making a diagnosis. It is likely that, as we understand more about the nature of the malignant process, we shall be able to use genetic techniques to enhance considerably both diagnostic and prognostic precision.

DNA↗
PubMed1999

Molecular pathology of multiple endocrine neoplasia type I: two novel germline mutations and updated classification of mutations affecting MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined development of tumors in several endocrine glands and other tissues. The MEN1 gene was recently identified and isolated by positional cloning. This gene was screened in two unrelated MEN1 Spanish kindreds (with four affected members and seven asymptomatic members) using single-strand conformation polymorphism, DNA sequencing, and restriction enzyme analysis. Two novel germline mutations were identified: a missense in exon 2 (H139R) and a splice-site in intron 9 (1461-2A>C). These findings allowed us to identify the MEN1 carriers among the seven asymptomatic members analyzed. An updated review of the mutations and polymorphisms found in the analysis of the MEN1 gene is provided. The report of all germline mutations causing MEN1 and easy access to this updated information are both of special diagnostic interest, because this greatly facilitates the task of attributing the disorder to a specific mutation found in a given MEN1 family. This is especially helpful in the critical differentiation of missense mutations from nonsynonymous polymorphisms that fit the pattern of segregation of the disease, but do not cause it.

Adolescent↗
PubMed2001

Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism.

Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (beta(2)-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the newborn.

Adolescent↗
PubMed2005

AutoFACT: an automatic functional annotation and classification tool.

BACKGROUND: Assignment of function to new molecular sequence data is an essential step in genomics projects. The usual process involves similarity searches of a given sequence against one or more databases, an arduous process for large datasets. RESULTS: We present AutoFACT, a fully automated and customizable annotation tool that assigns biologically informative functions to a sequence. Key features of this tool are that it (1) analyzes nucleotide and protein sequence data; (2) determines the most informative functional description by combining multiple BLAST reports from several user-selected databases; (3) assigns putative metabolic pathways, functional classes, enzyme classes, GeneOntology terms and locus names; and (4) generates output in HTML, text and GFF formats for the user's convenience. We have compared AutoFACT to four well-established annotation pipelines. The error rate of functional annotation is estimated to be only between 1-2%. Comparison of AutoFACT to the traditional top-BLAST-hit annotation method shows that our procedure increases the number of functionally informative annotations by approximately 50%. CONCLUSION: AutoFACT will serve as a useful annotation tool for smaller sequencing groups lacking dedicated bioinformatics staff. It is implemented in PERL and runs on LINUX/UNIX platforms. AutoFACT is available at http://megasun.bch.umontreal.ca/Software/AutoFACT.htm.

Acanthamoeba castellanii↗
PubMed1988

Classification of bovine aortic alpha-1 adrenoceptors by the criteria of ligand affinity and molecular mass.

[3H]Prazosin bound to a single class of alpha-1 adrenoceptors in bovine aortic membranes with a Kd of 25 pM. Digitonin solubilized 30% of the receptors as assayed by specific [3H] prazosin binding. The rank order potency of displacing ligands was the same for both membrane-bound and soluble alpha-1 adrenoceptors [prazosin greater than phentolamine greater than yohimbine and (-)-epinephrine = (-)-norepinephrine much greater than (+)-norepinephrine]. Prazosin had a significantly lower affinity for the soluble receptor, whereas the other adrenergic ligands had the same affinity for both forms of the receptor. The alpha-1 adrenoceptor was affinity-labeled with 2-[4-(4-azido-3-[125I]iodobenzoyl)piperazin-1-yl]-4-amino-6,7- dimethoxyquinazoline and analyzed by reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The molecular mass of the receptor binding subunit in both bovine aorta and rat liver was found to be 86,000 MW. It is concluded from this study that bovine aortic alpha-1 adrenoceptors have pharmacologic and biochemical characteristics similar to those in other tissues.

Affinity Labels↗
PubMed2004

Management of recurrent endometrial carcinoma.

Management of recurrent endometrial carcinoma has traditionally focused on providing targeted adjuvant therapy in select groups of patients based on their risk factors. Major progress has been made over the last two decades in identifying these clinical-pathological risk factors, which has led to the classification of patients into different risk groups. Patients with high-risk factors are generally treated with adjunctive radiation therapy immediately following surgery to minimize the incidence of recurrence. Those patients identified as low-risk generally receive no further treatment. Patients with intermediate-risk factors are individualized either to receive adjunctive therapy or not to receive further therapy based on institutional bias. Review of the literature suggests this traditional treatment strategy may reduce local recurrence, but fails to improve overall survival. Further studies to identify molecular based biomarkers may improve current classification of risk factors and the selection of patients for adjunctive therapy. Once the recurrence takes place, loco-regional disease can be treated with radiation therapy with reasonable success. Targeted radiotherapy and several cytotoxic chemotherapeutic agents are effective in the treatment of systemic recurrent disease. Hormonal therapy has also been demonstrated to be useful in selected group of patients for palliative purpose. The current areas of controversy and debate include the efficacy of adjunctive therapy, mode of therapy, timing of therapy, and issues related to surgical staging of patients as required by the current FIGO staging system.

Chemoprevention↗
PubMed2002

[Molecular diagnostic tools in gastroenterology].

Molecular biology has become an integral part of modern medicine. Novel molecular methods have yielded great progress in early detection, classification and management of a variety of diseases. This review discusses principles and applications of molecular diagnostic tools in the field of gastroenterology.

Adolescent↗
PubMed2006

Detection of the bcl-2 t(14;18) translocation and proto-oncogene expression in primary intraocular lymphoma.

PURPOSE: Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells. METHODS: Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis. RESULTS: Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger. CONCLUSIONS: PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lymphomas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profiling, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease.

Adaptor Proteins, Signal Transducing↗
PubMed1996

High-resolution diffusion and relaxation edited one- and two-dimensional 1H NMR spectroscopy of biological fluids.

A new approach to the characterization of biomolecules in whole biological fluids is presented based on simplification of 1H NMR spectra by utilizing differences in molecular diffusion coefficients alone and combinations of relaxation and diffusion parameters. New NMR pulse sequences incorporating both spectral editing features together with solvent water resonance elimination are presented. The methods are exemplified using whole human blood plasma, and it is shown that it is possible to obtain NMR spectra of the slowly diffusing species (generally large molecules) by diffusion editing, the slowly relaxing species (generally small molecules) by spin relaxation editing, or spectra showing any range of molecular mobility using a combination of the two methods. The diffusion-based editing methods are also applicable to the selection of resonances in two-dimensional NMR spectroscopy of biofluids, and we show this for the first time by the production of 1H-1H diffusion-edited TOCSY spectra of human blood plasma where the resonance intensities are weighted according to the molecular diffusion coefficient. In this case, by measuring a diffusion-edited 1H-1H TOCSY NMR spectrum of plasma, it is possible to obtain signals from only the macromolecular components, and this may be of benefit in the analysis of blood lipoproteins. In complex biofluids, the combination of diffusion and relaxation editing brings about considerable spectral simplification leading to an easier resonance assignment process. We also demonstrate the production of 1H NMR spectra with intensities corresponding to diffusion coefficient rather than number of protons, and this opens up new possibilities for pattern recognition classification of samples based on altered molecular mobility features of biofluid components.

Blood↗
PubMed2002

[New WHO classification of myelodysplastic syndromes. The consequences].

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders. Diagnosis and classification of MDS are based on morphological features of blood and bone marrow cells. The F.A.B. classification is widely used, but remains unclear in some cases of MDS. A World Health Organization (WHO) working group proposed a new classification of MDS, to improve the homogeneity of the different categories in term of physiopathology and prognosis. The new WHO classification incorporated some clinical and etiological data, and the results of cytogenetical or molecular analysis. The homologies and the differences between these two classification are showed, and the clinical consequences of the new classification are discussed.

Bone Marrow Cells↗