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At least 217 records · Page 12Linked to original sources
PubMed1999

Genetic and phenotypic changes accompanying the emergence of epizootic subtype IC Venezuelan equine encephalitis viruses from an enzootic subtype ID progenitor.

Recent studies have indicated that epizootic Venezuelan equine encephalitis (VEE) viruses can evolve from enzootic, subtype ID strains that circulate continuously in lowland tropical forests (A. M. Powers, M. S. Oberste, A. C. Brault, R. Rico-Hesse, S. M. Schmura, J. F. Smith, W. Kang, W. P. Sweeney, and S. C. Weaver, J. Virol. 71:6697-6705, 1997). To identify mutations associated with the phenotypic changes leading to epizootics, we sequenced the entire genomes of two subtype IC epizootic VEE virus strains isolated during a 1992-1993 Venezuelan outbreak and four sympatric, subtype ID enzootic strains closely related to the predicted epizootic progenitor. Analysis by maximum-parsimony phylogenetic methods revealed 25 nucleotide differences which were predicted to have accompanied the 1992 epizootic emergence; 7 of these encoded amino acid changes in the nsP1, nsP3, capsid, and E2 envelope glycoprotein, and 2 were mutations in the 3' untranslated genome region. Comparisons with the genomic sequences of IAB and other IC epizootic VEE virus strains revealed that only one of the seven amino acid changes associated with the 1992 emergence, a threonine-to-methionine change at position 360 of the nsP3 protein, accompanied another VEE virus emergence event. Two changes in the E2 envelope glycoprotein region believed to include the major antigenic determinants, both involving replacement of uncharged residues with arginine, are also candidates for epizootic determinants.

Amino Acid Sequence↗
PubMed1988

Latent hepatitis B virus infection with full-length viral genome in a patient serologically immune to hepatitis B virus infection.

The presence, state, physical structure and cellular localization of hepatitis B virus (HBV) DNA were investigated in a patient with hepatitis B surface antigen (HBsAg)-negative chronic liver disease. HBV serology was positive for antibodies to hepatitis B core antigen (anti-HBc), to hepatitis B e antigen (anti-HBe) and to HBsAg (anti-HBs); no HBV DNA was detectable in serum. Southern blot analyses of DNA extracted from the liver demonstrated free monomeric HBV DNA as two distinct species: a predominant species of fully double-stranded relaxed circular molecules and a minor species of linear molecules of 3.2 kilobase pairs (kbp) length. Restriction enzyme analyses identified the HBV genome as HBsAg subtype adw2. Cell fractionation studies further revealed that the free viral DNA species were localized exclusively in liver cell nuclei. These findings in a patient serologically immune to HBV infection demonstrate that in hepatocytes HBV can establish a latent infection, characterized by the extrachromosomal presence of a full-length viral genome without production of infectious virus or synthesis of viral antigens.

Aged↗
PubMed2026

Molecular Profiling Across 80,000 Patients With Lung Cancer.

INTRODUCTION: Biomarker testing is an essential component of optimal therapeutic management in NSCLC, enabling the use of both Food and Drug Administration-approved and emerging targeted therapies. Despite well-established biomarker testing guidelines and the availability of many approved targeted therapies, a substantial proportion of patients with advanced NSCLC are not benefiting from precision oncology. In this study, we analyze the distribution of actionable genomic alterations across histologic subtypes and clinicodemographic subgroups of NSCLC using data in 82,328 samples profiled with a single comprehensive genomic profiling assay, aiming to support universal molecular testing across all NSCLC subtypes to ensure equitable access to available therapeutics. METHODS: This is an observational retrospective analysis on histologically confirmed NSCLC cases tested with comprehensive genomic profiling by next-generation sequencing between 2014 and 2022 using Foundation One/Foundation CDx. All cases were centrally reviewed by board-certified anatomic pathologist to determine histologic type and subtype. RESULTS: A total of 82,328 patients with NSCLC were included. An actionable genomic alteration (GA) was found in 35.1% of the cases. Lung adenocarcinoma (LUAD) and adenosquamous carcinoma were more frequently associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (27.6%), large cell (21.1%), and squamous cell (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutation (mut) frequency (9.95% versus 2.43% in LUAD). Tumor mutation burden more than or equal to 10 mut/Mb was associated with histology (50.91% in large cell, 40.79% in not otherwise specified, 39.08% in squamous cell, and 36.30% in sarcomatoid versus 31.22% in LUAD and 29.22% in adenosquamous carcinoma). Patients with actionable GA had usually a low tumor mutation burden (80.88%). A significant correlation (p < 0.005) between age and actionable GA was reported for BRAF/ERBB2 muts, ALK/RET/ROS1 rearrangements, and MET amplification. EGFR actionable muts and KRAS G12C were more frequently observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation for EGFR actionable muts and South/East Asia and America, but not for other GA. CONCLUSIONS: This is the largest NSCLC data set analyzed for biomarker distribution across histologies, age, sex, and genetic ancestry. This data set confirms sufficient enough biomarker prevalence across many histologic subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.

Humans↗
PubMed1998

Extent of antigenic diversity in the V3 region of the surface glycoprotein, gp120, of human immunodeficiency virus type 1 group M and consequences for serotyping.

Human immunodeficiency virus type 1 (HIV-1) may be studied by molecular or immunological approaches. Most analyses have been performed by genetic comparison of isolates and have led to the definition of clades or subtypes within the major (M) group of HIV-1. Five subtypes (A to E) were initially identified by comparison of genomic sequences. Four new subtypes (F to I) were identified more recently. Amino acid differences in the immunogenic V3 loop between isolates have also been studied, leading to a phenetic classification of at least 14 clusters (1 to 14) of sequences (B. T. M. Korber, K. McInnes, R. F. Smith, and G. Myers, J. Virol. 68:6730-6744, 1994). In this study, we compared the antigenicity of the V3 consensus sequences defined by phylogenetic analysis to the antigenicity of those defined by phenetic analysis. We used a recently developed subtype-specific enzyme immunoassay (SSEIA) that uses the principle of blocking with an excess of peptide in the liquid phase. Two SSEIAs were performed, the first with five V3 sequences defined by phylogenetic analysis and the second with 14 V3 sequences defined by phenetic analysis. A total of 168 HIV-1 sera taken from seropositive individuals from seven different countries or regions were studied. Experimental and statistical data, including correlation matrix and cluster analyses, demonstrated associations between the genetic subtypes and phenetically associated groups. Most of these were predicted by Korber et al. (J. Virol. 68:6730-6744, 1994) by theoretical analysis. We also found that V3 sequences can be grouped into between three and five antigenically unrelated categories. Residues that may be responsible for major antigenic differences were identified at the apex of the V3 loop, within the octapeptide xIGPGxxx, where x represents the critical positions. Our study provides evidence that there is a limited number of V3 serotypes which could be easily monitored by serological assays to study the diversity and dynamics of HIV-1 strains.

Amino Acid Sequence↗
PubMed2006

Gene expression patterns associated with p53 status in breast cancer.

BACKGROUND: Breast cancer subtypes identified in genomic studies have different underlying genetic defects. Mutations in the tumor suppressor p53 occur more frequently in estrogen receptor (ER) negative, basal-like and HER2-amplified tumors than in luminal, ER positive tumors. Thus, because p53 mutation status is tightly linked to other characteristics of prognostic importance, it is difficult to identify p53's independent prognostic effects. The relation between p53 status and subtype can be better studied by combining data from primary tumors with data from isogenic cell line pairs (with and without p53 function). METHODS: The p53-dependent gene expression signatures of four cell lines (MCF-7, ZR-75-1, and two immortalized human mammary epithelial cell lines) were identified by comparing p53-RNAi transduced cell lines to their parent cell lines. Cell lines were treated with vehicle only or doxorubicin to identify p53 responses in both non-induced and induced states. The cell line signatures were compared with p53-mutation associated genes in breast tumors. RESULTS: Each cell line displayed distinct patterns of p53-dependent gene expression, but cell type specific (basal vs. luminal) commonalities were evident. Further, a common gene expression signature associated with p53 loss across all four cell lines was identified. This signature showed overlap with the signature of p53 loss/mutation status in primary breast tumors. Moreover, the common cell-line tumor signature excluded genes that were breast cancer subtype-associated, but not downstream of p53. To validate the biological relevance of the common signature, we demonstrated that this gene set predicted relapse-free, disease-specific, and overall survival in independent test data. CONCLUSION: In the presence of breast cancer heterogeneity, experimental and biologically-based methods for assessing gene expression in relation to p53 status provide prognostic and biologically-relevant gene lists. Our biologically-based refinements excluded genes that were associated with subtype but not downstream of p53 signaling, and identified a signature for p53 loss that is shared across breast cancer subtypes.

Base Sequence↗
PubMed2001

Expression, purification, immunological characterization and application of Escherichia coli-derived hepatitis C virus E2 proteins.

The envelope glycoprotein E2 of hepatitis C virus (HCV) has been shown to bind human target cells. Anti-E2 antibodies have been associated with both recovery from natural infection in humans and protection from challenge with homologous HCV in chimpanzees. Therefore E2 has become a major target for the development of anti-HCV vaccines. Two E2 fragments [amino acids (aa) 450-565 and aa 385-565] derived from a subtype 1b HCV genome were expressed as N-terminally hexahistidine-tagged proteins in Escherichia coli and purified to over 85% purity. Both proteins were specifically recognized by homologous hepatitis-C-patient's serum on Western blotting, suggesting that these E. coli-derived E2 proteins displayed E2-specific antigenicity. E2-116 (aa 450-565) elicited strong antibody responses in BALB/c mice and rabbits. Rabbit antiserum raised against renatured E2-116 (R(E2-116R)) was able to recognize subtype 1b and 1a E2 glycoproteins expressed in mammalian cells on Western blotting. E2-181 (aa 385-565) reacted with 40% of anti-HCV(+) patients' sera in ELISA. R(E2-116R) and E2-181 were successfully used in preliminary modified vaccinia virus Ankara- and DNA-based E2 vaccine studies for detecting antigen expression in vitro and assessing induced humoral immune responses in mice. The E2 proteins and rabbit antiserum reported here could find wider applications in the development of effective diagnostic, prophylactic and therapeutic measures against HCV.

Animals↗
PubMed2004

Birth-and-death evolution with strong purifying selection in the histone H1 multigene family and the origin of orphon H1 genes.

Histones are small basic nuclear proteins with critical structural and functional roles in eukaryotic genomes. The H1 multigene family constitutes a very interesting histone class gathering the greatest number of isoforms, with many different arrangements in the genome, including clustered and solitary genes, and showing replication-dependent (RD) or replication-independent (RI) expression patterns. The evolution of H1 histones has been classically explained by concerted evolution through a rapid process of interlocus recombination or gene conversion. Given such intriguing features, we have analyzed the long-term evolutionary pattern of the H1 multigene family through the evaluation of the relative importance of gene conversion, point mutation, and selection in generating and maintaining the different H1 subtypes. We have found the presence of an extensive silent nucleotide divergence, both within and between species, which is always significantly greater than the nonsilent variation, indicating that purifying selection is the major factor maintaining H1 protein homogeneity. The results obtained from phylogenetic analysis reveal that different H1 subtypes are no more closely related within than between species, as they cluster by type in the topologies, and that both RD and RI H1 variants follow the same evolutionary pattern. These findings suggest that H1 histones have not been subject to any significant effect of interlocus recombination or concerted evolution. However, the diversification of the H1 isoforms seems to be enhanced primarily by mutation and selection, where genes are subject to birth-and-death evolution with strong purifying selection at the protein level. This model is able to explain not only the generation and diversification of RD H1 isoforms but also the origin and long-term persistence of orphon RI H1 subtypes in the genome, something that is still unclear, assuming concerted evolution.

Amino Acid Sequence↗
PubMed1995

Coding strategy of the S and M genomic segments of a hantavirus representing a new subtype of the Puumala serotype.

The hantavirus strain Vranica was previously reported to have been isolated from a bank vole in Bosnia-Hercegovina and associated with the occurrence of hemorrhagic fever with renal syndrome (HRFS) in humans. The complete cDNA nucleotide sequences of the small (S) and medium (M) genomic RNA segments of this virus were determined. Major open reading frames were found in the S and M segment between nucleotide positions 43 and 1341 coding for a polypeptide of 433 amino acid residues and between nucleotide positions 41 and 3,484 coding for 1,148 amino acid residues, respectively. The analysis and the alignment of the nucleotide and the derived amino acid sequences with known sequences of other hantavirus strains demonstrate that Vranica resembles Swedish strains and represents a new virus subtype of the Puumala serotype distinct from the subtypes represented by virus strains CG18-20 and Sotkamo.

Amino Acid Sequence↗
PubMed2001

Chromosomal aberrations in sporadic pituitary tumors.

Pituitary adenomas are common intracranial neoplasms that may be hormone-secreting or nonfunctional. Genetic defects associated with some pituitary tumors have been identified, although our understanding of the underlying molecular mechanisms remains incomplete. We have studied 75 sporadic pituitary tumors, representing the major clinical subtypes, by comparative genomic hybridization (CGH) with the aim of assessing for DNA copy number changes. CGH revealed chromosomal imbalances in 34 adenomas (45.3%), whereby gains were 4.9 times more frequently observed than losses. Most of the genetic alterations detected by CGH affected entire chromosomes (108/131, 82.4%). Gain of genetic material was observed predominantly on chromosomes X (24/75, 32%), 19 (12/75, 16%), 12 (6/75, 6.7%), 7 and 9 (5/75, 6.7%), whereas loss of DNA sequences most frequently affected chromosomes 11 (4/75, 5.3%), 13 and 10 (3/75, 4%). There were no significant differences in the CGH results for the individual clinical subtypes of pituitary tumors. These results reveal a nonrandom pattern of chromosomal alterations in pituitary tumors, in particular gains of entire chromosomes, and this may contribute to the development of such neoplasms.

Adenoma↗
PubMed2004

Isolation and identification of swine influenza recombinant A/Swine/Shandong/1/2003(H9N2) virus.

Ten influenza virus isolates were obtained from infected pigs from different places in Shandong province showing clinical symptoms from October 2002 to January 2003. All 10 isolates were identified in China's National Influenza Research Center as influenza A virus of H9N2 subtype. The complete genome of one isolate, designated A/Swine/Shandong/1/2003(H9N2), was sequenced and compared with sequences available in GenBank. The results of analyses indicated that the sequence of A/Swine/Shandong/1/2003(H9N2) was similar to those of several chicken influenza viruses and duck influenza viruses recently prevalent in South China. According to phylogenetic analysis of the complete gene sequences, A/Swine/Shandong/1/2003(H9N2) possibly originated from the reassortment of chicken influenza viruses and duck influenza viruses. It was found that the amino acid sequence at the HA cleavage site in Sw/SD/1/2003 is R-S-L-R-G, differing clearly from that of other H9N2 subtype isolates of swine influenza and avian influenza, which is R-S-S-R-G.

Amino Acid Sequence↗
PubMed1998

Molecular biological characterization of adenovirus DNA.

The agarose gel electrophoresis of DNA, the ethidium bromide fluorescence detection of DNA fragments and restriction endonucleases were discovered at the end of the '60s. The methodological progress enabled institutions equipped with less sophisticated technology to achieve also unique experimental and scientific results in the field of viral DNA research. The team working on virus DNA within the adenovirus research group has constructed several new restriction endonuclease maps of the genomes of human and animal adenoviruses; contributed to the methodology of the determination of specific endonuclease sites, and genome polarity; discovered new restriction endonucleases, adenovirus subtypes, new empty capsid, and genome subpopulations; participated in cooperations leading to novel, although hypothetical approaches in AIDS therapy, taxonomic definition of viruses, and evolutionary origins of adenovirus replication and encapsidation strategy.

Adenoviridae↗
PubMed2000

Intersubtype recombinant HIV type 1 involving HIV-MAL-like and subtype H-like sequence in four Norwegian cases.

Suspected epidemiological links between three cases of human immunodeficiency virus type 1 (HIV-1) infection were verified by the finding of a shared unique virus genotype. A probable male index case was not available for testing. Case 1 was a female sexual partner of the index case. Case 2 was an adult son of case 1. Case 3 was a female sexual partner of case 2. The link to the index case was substantiated by the subsequent finding of another female sexual contact of the index case, harboring the same HIV-1 genotype as the three other cases. To characterize the genotype further, the complete provirus nucleotide sequence was obtained directly from blood cell DNA of case 3. HIV cultivated from case 3 demonstrated CCR5 dependence, an extreme slow-low phenotype, and some genotypic features not present in its directly sequenced counterpart. Most of the gag, pol, and vif genes of these viruses clustered with one of the earliest African HIV-1 strains, MAL, previously classified as a recombinant between the subtypes A, D, and I. Most of the rest of the genome was related to subtype H, albeit with less than 90% identity in most regions. These viruses are the only ones shown to display extensive similarity with MAL in the gag-pol region and among the first HIV-1 recombinants described involving subtype H. We postulate that the gag-pol genes of MAL and these viruses are derived from a common ancestor that is not necessarily intersubtype recombinant in the pol region.

Adult↗
PubMed2001

Subtyping of oligo-astrocytic tumours by comparative genomic hybridization.

Oligo-astrocytic tumours (OAs) histologically show both oligodendroglial and astrocytic differentiation. Unequivocal criteria for delineation of OAs from pure oligodendroglial (Os) and astrocytic (As) tumours and for grading of OAs are lacking. Molecular genetic analysis may allow for a better characterization of OAs and thereby guide prognostic and therapeutic decisions. Comparative genomic hybridization (CGH) was performed on 39 gliomas with variable phenotypic expression of histological features characteristic of both astrocytic and oligodendroglial differentiation. The results show that OAs are genetically more heterogeneous than Os. In addition to the "-1p/-19q" and "+7/-10" subtypes that have been previously recognized, two additional genetic subtypes, "intermediate" and "other", were identified in the present study. "Intermediate" OAs likely represent progression from "-1p/-19q" tumours. The "other" subtype appears to represent an additional, heretofore unrecognized, genetic pathway(s). Application of rigorously "strict" histopathological criteria, as opposed to "relaxed" criteria, for the selection of oligo-astrocytic tumours resulted in a higher percentage of "-1p/-19q" tumours, but some "-1p/-19q" tumours might be missed. The results suggest that molecular genetic analysis is a useful and valid additional tool for the classification of gliomas, particularly for the significant subset of tumours in which subjective histopathological criteria are insufficient for an unequivocal distinction between Os, As, and mixed OAs.

Adult↗
PubMed1996

Involvement of distinct receptors in the actions of extracellular uridine nucleotides.

The P2 purinoceptors were initially defined as a family of receptors responsive to extracellular adenine nucleotides. In the late 1980s, it became clear that extracellular uridine nucleotides are also able to modulate cell function. The existence of a nucleotide receptor, common to ATP and UTP, was suggested by indirect pharmacological arguments (for instance the lack of additivity and the cross-desensitization of the responses to the two nucleotides) and later demonstrated by the cloning of a P2U receptor equally responsive to ATP and UTP. Vascular endothelial cells are a paradigm of cells on which both ATP and UTP exert physiologically relevant effects (stimulation of prostacyclin and nitric oxide release). Their response to nucleotides is mediated by two distinct receptors, both coupled to phospholipase C: a specific purinoceptor responsive to ATP and ADP (P2Y) and a nucleotide receptor responsive to ATP and UTP (P2U). We have recently cloned from the human genome a new subtype of receptor (tentatively called P2Y4), which is structurally related to the P2U receptor. Functional expression revealed its coupling to phospholipase C and its selective responsiveness to UTP and UDP. According to the new nomenclature, the P2 receptors that are coupled to G proteins belong to the P2Y family. It now appears that this family encompasses specific purinoceptors (P2Y1, formerly called P2Y), nucleotide receptors common to ATP and UTP (P2Y2, previously P2U) and selective pyrimidinoceptors (P2Y4). The existence of these pyrimidinoceptors suggests that uridine nucleotides may play a role as intercellular mediators, independently from adenine nucleotides.

Animals↗
PubMed1996

Recombinant human granulocyte colony-stimulating factor reduces hepatitis C virus replication in mononuclear cells from chronic hepatitis C patients.

Hepatitis C virus infects mononuclear leukocytes of patients with chronic hepatitis C. Treatment with rhG-CSF led to a dose-related reduction in the genomic and antigenomic hepatitis C viral strands in cultures of mitogen-stimulated, naturally-infected peripheral blood mononuclear cells from patients with chronic hepatitis C. Hepatitis C virus genomic strand of subtype 1b was suppressed in 5 of 11 cases, and concurrently with suppression of the viral antigenomic strand in two of them. The treatment also resulted in a significantly increased release of interleukin 6, but not of other cytokines. However, the biological response of hepatitis C virus-infected mononuclear cells to treatment with recombinant human granulocyte colony-stimulating factor was unrelated to any particular pattern of cytokine production.

Antiviral Agents↗
PubMed1988

Mast cell polymorphisms. Present concepts, future directions.

Although mast cells are widely distributed in the body, their functions are poorly known. The elucidation of mast cell function is complicated by growing evidence that mast cells are heterogeneous. Recent studies of mast cell ontogeny suggest that microenvironmental stimuli control the phenotypic expression of parts of the genome leading to subtype differences in a common lineage. Mast cells influence cell proliferation, differentiation, and activation in a range of target cells, although until recently they were considered important only in immediate hypersensitivity. However, they function in delayed-type hypersensitivity, potentiate cytotoxicity of eosinophils and macrophages, and are cytotoxic for certain targets themselves. Mast cell mediators influence blood flow and vascular permeability and facilitate angiogenesis. Numerous mast cell mediators are immunoregulatory. In vitro experiments have begun to investigate the role of mast cells in fibrotic diseases. Further knowledge of mast cell heterogeneity will provide the basis for new therapies in inflammatory diseases of the intestine and other organs.

Colitis, Ulcerative↗
PubMed2006

Development and application of Multiple-Locus Variable number of tandem repeat Analysis (MLVA) to subtype a collection of Listeria monocytogenes.

In this study we report the development and application of a Multiple-Locus Variable number of tandem repeat Analysis (MLVA) strategy for subtyping Listeria monocytogenes. Genome profiles of a collection of forty-five food-borne L. monocytogenes isolates were compared using MLVA. These isolates were obtained as part of an active surveillance programme of foods in the south-east region of Ireland. MLVA successfully discriminated amongst the isolates. The method was easy to perform, relatively fast and could be deployed in any molecular laboratory with basic laboratory equipment. This approach is a valuable tool, which has the capability to provide comparable results when compared with other more established typing methods, including pulsed-field gel electrophoresis (PFGE).

Bacterial Typing Techniques↗