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PubMed1997

Genotypic distribution of hepatitis C virus in different regions of Thailand.

The genotypic distribution of hepatitis C virus (HCV) isolated from blood donors from four major regions of Thailand was studied by reverse hybridization assays. PCR-amplified products from the 5' noncoding and core regions of the viral genome were hybridized to genotype- and subtype-specific probes which were immobilized on the nitrocellulose membrane. Of 332 anti-HCV-positive plasma samples studied, 71% contained HCV RNA. HCV genotype 3a was the most prevalent genotype (39%), followed by genotype 1b (20%) and genotype 6 group variants (18%). HCV genotype 1a was identified among 9% of all isolates. Other genotypes (genotype 1 which was neither 1a nor 1b, genotype 3b, and an unclassified genotype) were uncommon. There was no difference in the mean age of the donors infected with different HCV genotypes. The genotypic distribution pattern of HCV was similar among HCV isolates from different regions of Thailand.

Genes, Viral↗

PubMed2026

Patient-derived organoids predict responses to chemotherapy and PARP inhibitors in advanced ovarian cancer.

BACKGROUND: While tumor organoids hold promise for personalized medicine, clinical validation of epithelial ovarian cancer (EOC) organoids as predictors of therapeutic efficacy-particularly for PARP inhibitors (PARPi)-remains unestablished. METHODS: Patient-derived organoids (PDOs) were established from treatment-naive EOC specimens and characterized by H&E staining, immunohistochemistry, and whole-exome sequencing. Drug sensitivity testing (DST) was performed using carboplatin, paclitaxel, and PARPi (olaparib and niraparib). Clinical homologous recombination deficiency (HRD) status was assessed by tumor sequencing. Organoid responses were prospectively compared to patient outcomes after first-line chemotherapy (carboplatin/paclitaxel) and PARPi maintenance. RESULTS: PDOs were successfully established from 21 of 30 patients (70%) across multiple EOC subtypes and preserved the histopathological features and genomic landscapes of their corresponding primary tumors. Organoid-based DST accurately predicted responses to first-line carboplatin/paclitaxel, with a sensitivity of 100% (95% CI 62.88-100%), specificity of 66.67% (95% CI 12.53-98.23%), accuracy of 91.67% (95% CI 61.52-99.79%), AUC of 0.95 (95% CI 0.85-1.00), and Cohen's kappa of 0.75 (95% CI 0.30-1.00). In evaluating PARPi response, organoids revealed discrepancies between genomic HRD status and actual drug responses. One HRD-positive PDO was PARPi-resistant, consistent with patient non-response, while two HRR-proficient PDOs showed PARPi sensitivity and corresponding clinical benefit. CONCLUSIONS: EOC-derived PDOs provide a robust platform for predicting chemotherapy response and offer added value in assessing PARPi efficacy beyond genomic profiling. Combination of organoid-based testing with genomic analysis may improve precision treatment strategies in EOC.

Humans↗

PubMed1999

Mapping of five subtype genes for muscarinic acetylcholine receptor to mouse chromosomes.

Muscarinic acetylcholine receptors in mammals consist of five subtypes (M1-M5) encoded by distinct genes. They are widely expressed throughout the body and play a variety of roles in the peripheral and central nervous systems. Although their pharmacological properties have been studied extensively in vitro, colocalization of the multiple subtypes in each tissue and lack of subtype-specific ligands have hampered characterization of the respective subtypes in vivo. We have mapped mouse genomic loci for all five genes (Chrm1-5) by restriction fragment length variant (RFLV) analyses in interspecific backcross mice. Chrm1, Chrm2, and Chrm3 were mapped to chromosome (Chr) 19, 6, and 13, respectively. Both Chrm4 and Chrm5 were mapped to Chr 2. Although a comparison of their map positions with other mutations in their vicinities suggested a possibility that the El2 (epilepsy 2) allele might be a mutation in Chrm5, sequencing analyses of the Chrm5 gene in the El2 mutant mice did not support such a hypothesis.

Animals↗

PubMed2004

Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma.

We evaluated amplification and overrepresentation of CDK4, MDM2, GLI and SAS genes of the 12q13-15 region, in a group of soft tissue sarcomas including leiomyosarcomas (LMS), alveolar rhabdomyosarcomas (ARMS) and embryonal (anaplastic and classic variants) rhabdomyosarcomas (ERMS), to ascertain genomic alterations and possible differences within histologic subtypes of rhabdomyosarcoma (RMS). Quantitative real-time PCR was performed on DNA samples from 29 LMS, 9 ARMS, 7 anaplastic ERMS and 6 classic ERMS. Alteration of one or more of the 12q13-15 genes was revealed in 13/29 LMS (45%) and 12/22 RMS (54%) including 5/9 ARMS (56%), 5/7 anaplastic ERMS (71%) and 2/6 classic ERMS (33%). The potential importance of overproduction of protein products in neoplastic development, led us also to study a possible high expression of cdk4, mdm2 and gli proteins in immunohistochemical staining experiments on paraffin-embedded tissue samples of the same cases. Among LMS and RMS most cases with CDK4, MDM2 and GLI gene alterations also showed a simultaneous high expression of the relative protein. In summary, these results indicate that amplification or overerepresentation of genes at 12q13-15 region involve both LMS and RMS. Moreover these genes alterations reveal predominantly in the alveolar and in the anaplastic variant of the embryonal subtype. These two seem to have a more similar behavior than anaplastic and classic embryonal that are classified in the same subtype.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2026

The role of stem cells in pituitary tumour formation.

Pituitary tumours are intracranial neoplasms that pose significant clinical challenges due to their potential for recurrence, therapeutic resistance and resultant endocrine dysfunction and mass effects. In the normal anterior pituitary, resident pituitary stem cells (PSCs) contribute to tissue homeostasis and cellular turnover. The extent to which PSCs contribute to tumourigenesis is not known, but an increasing number of studies have been aiming to address this. In this review, we summarise current evidence implicating PSCs and tumour stem-like populations in pituitary tumour biology, including potential roles in tumour initiation, maintenance and progression. We outline practical criteria for defining tumour stem cells and evaluate findings from functional studies of human tumours, emerging single-cell and spatial transcriptomic datasets and murine lineage-tracing models. We also provide a curated overview of published single-cell RNA sequencing studies of pituitary tumours, highlighting reported stem/progenitor populations and transcriptional signatures across tumour subtypes and propose a framework for future genomic analyses. Finally, we discuss the translational implications of these findings, including the potential for targeting stem-like populations and their associated signalling pathways.

Humans↗

PubMedDate not supplied

Detection of HTLV-IIa blood donors in an urban area of the Amazon Region of Brazil (Belém, PA).

The human lymphotropic viruses type I (HTLV-I) and type II (HTLV-II) are members of a group of mammalian retroviruses with similar biological properties, and blood transfusion is an important route of transmission. HTLV-I is endemic in a number of different geographical areas and is associated with several clinical disorders. HTLV-II is endemic in several Indian groups of the Americas and intravenous drug abusers in North and South America, Europe and Southeast Asia. During the year of 1995, all blood donors tested positive to HTLV-I/II in the State Blood Bank (HEMOPA), were directed to a physician and to the Virus Laboratory at the Universidade Federal do Pará for counselling and laboratory diagnosis confirmation. Thirty-five sera were tested by an enzyme immune assay, and a Western blot that discriminates HTLV-I and HTLV-II infection. Two HTLV-II positive samples were submitted to PCR analysis of pX and env genomic region, and confirmed to be of subtype IIa. This is the first detection in Belém of the presence of HTLV-IIa infection among blood donors. This result emphasizes that HTLV-II is also present in urban areas of the Amazon region of Brazil and highlights the need to include screening tests that are capable to detect antibodies for both types of HTLV.

Adult↗

PubMed1997

[Preliminary study on the inhibition of hepatitis B viral expression in vitro via specific receptors mediated ribozyme transfer].

Comparing with liposome and transferrin receptors (Tf-R) mediated transfection, a plasmid harboring foreign gene with hepatic specificity could be transfected via asialoglycoprotein receptors (ASGP-R) mediated endocytosis. A recombination plasmid pCMV-Ripc harboring a hammerhead ribozyme which aim at the pregenome RNA of HBV ayw subtype at the 1796 site in the genome was delivered into HepG2 cells (HBV transient transfected system) and 2.2.15 cells (HBV permanent transfected system) via receptors mediated gene transfer methods. ELISA results showed that the inhibition of HBsAg and HBeAg expression is 55.29% and 68.73% respectively when pCMV-Ripc is co-transfected with pUC-2HBV in HepG2 cells via ASGP-R mediated DNA transfer method. The result indicated that pCMV-Ripc is efficient to inhibit the expression of HBV antigen and ASGF-R method is a safe, liver-targeted delivery system, therefore it is possible to develop an in vivo gene therapy strategy aiming to the treatment of hepatic infectious disease.

Cell Line↗

PubMed2005

[Study on the molecular epidemiology of people infected with human immunodeficiency virus-1 in Shandong province].

OBJECTIVE: To study the distribution of human immunodeficiency virus-1 (HIV-1) strains subtypes in Shandong province and to study their source in order to predict the epidemic trend. METHODS: Epidemiological investigation was made and 93 DNA fragments of HIV-1 env, gag, tat gene were amplified by nested polymerase chain reaction from people infected with HIV-1, in 2002 - 2003. Their C2-V3, P17/P24, 1st exon of tat and adjacent region were sequenced. RESULTS: Sequence analysis showed that there were 7 HIV-1 strains or circulating recombinant forms (CRFs), B' (n = 71), CRF01-AE (n = 9), CRF07-BC (n = 3), CRF08-BC (n = 3), B (n = 2), C (n = 2), CRF02-AG (n = 2). B' strains was the predominant which, covered 10 cities and 4 kinds of population including blood donors, blood receivers, spouses of the infected people and clients of the sex workers. CRF07-BC, CRF08-BC strains were identified in 5 cities, mainly from injecting drug users. CRF01-AE and other strains were found distributed in developed cities, among sex workers. CONCLUSION: There were many kinds of subtypes and CRFs of HIV and their genomes which generated obvious variation in Shandong province, suggesting that they might facilitate the spread of the disease in Shandong province.

Adolescent↗

PubMed1994

Activation of keratin 19 gene expression by a 3' enhancer containing an AP1 site.

We previously reported that the human keratin 19 (K19) gene was expressed in nonkeratinizing oral epithelial subtypes, and that the steady state K19 mRNA levels in different normal epithelial subtypes correlated with the levels of the retinoic acid receptor (RAR) beta-mRNA (Hu, L., Crowe, D. L., Rheinwald, J. G., Chambon, P., and Gudas, L. J. (1991) Cancer Res. 51, 3972-3981). To elucidate the mechanisms by which the K19 gene is differentially expressed in various epithelial subtypes, we isolated phage containing human K19 genomic DNA from a human placental library. Through transient transfection assays with various K19/CAT constructs that contain different portions of K19 genomic DNA, an enhancer sequence has been identified in the K19 3'-flanking region. In normal human epithelial cell strains, the activity of this enhancer correlates with K19 mRNA abundance. This enhancer activates both the K19 and TK basal promoters in HeLa cells. A high level of K19/CAT fusion mRNA was detected when this K19 3' enhancer sequence was present at the 3' end of the fusion gene whereas no K19/CAT fusion transcript was detected if this 3' K19 enhancer sequence was absent, suggesting that the 3' K19 enhancer is crucial for the positive regulation of K19 expression. Deletion analysis has permitted the localization of the enhancer to a 19-base pair sequence which contains an AP1 binding site (AGTCATCT). Point mutations within this AP1 site completely abolished K19 enhancer activity in HeLa cells. Co-transfections of a c-jun expression vector with K19/CAT reporter constructs demonstrated that c-jun was able to activate the K19 promoter via the 3' K19 enhancer. Collectively, these data indicate that a cis-acting AP1 element and its associated trans-acting effector proteins regulate expression of lineage-specific genes in epithelial cells.

Base Sequence↗

PubMedDate not supplied

[Human herpesvirus 8 and associated diseases: Kaposi's sarcoma, body cavity based lymphoma and multicentric Castleman disease: clinical and molecular epidemiology].

A new human virus belonging to the herpesvirinae family was recently isolated and characterized. This virus called human herpesvirus 8 is considered as the etiological agent or as a major cofactor of all the clinical forms (HIV associated or not) of Kaposi's sarcoma. HHV8 is also associated with rare B cell lymphomas called body cavity based lymphoma (BCBL) or Primary effusion lymphoma (PEL) occurring in the body cavities mainly in AIDS patients and of some cases of the multicentric form of Castleman's disease. Only preliminary data are available on the epidemiological characteristics (modes of transmission in endemic regions, geographical distribution ...) of the HHV8 infection but should rapidly beneficiate of the establishment of specific and reliable serological tests. Nevertheless, it appears that the HHV8 seroprevalence is very high (15 to 50%) in the adult general population of areas having a high incidence of Kaposi's sarcoma as some east african countries and at a lesser extend as some mediterranean areas as southern Italy or Greece. In the occidental world, the seroprevalence of HHV8 seems very low (0 to 5% in the blood donors) except in some populations at risk for sexually transmitted diseases especially in the homosexual male group. Preliminary data indicate the existence of a low genetic variability of HHV8 in several regions of its genome, with however the presence of molecular subtypes linked possibly to the geographical origin of the infected patients.

Castleman Disease↗

PubMed1999

Analyses of TT virus full-length genomic sequences.

Since the identification of TT virus, only one full-length and two near full-length sequences representing a single subtype of the virus have been reported. In order to understand further the nature of the TT virus genome, nine of the most divergent TT virus sequences have been extended to full-length or near full-length. Phylogenetic analysis demonstrated that these sequences represent three distinct TT virus genotypes and two subtypes. A high degree of nucleotide sequence variability (approximately 30%) was observed across the genomes with several significantly more divergent regions. Three conserved ORFs were identified, none of which shared significant amino acid sequence identity to sequences present in public databases. Additionally, sequence motifs, such as those necessary for protein translation and for rolling circle replication, were found to be partially conserved between all TT virus isolates.

DNA Viruses↗

PubMed2002

Heterosexually acquired CRF01_AE/B recombinant HIV type 1 found in Thailand.

CRF01_AE and subtype B are circulating in Thailand and the strains have become intermixed in some high-risk groups, establishing the possibility of intersubtype recombination. The first such recombinant, mostly B with gp120 from CRF01_AE, was recently identified. Here we report a heterosexually acquired recombinant of different structure, with most of the genome from CRF01_AE but almost the entire envelope from subtype B. Surveillance by V3 serotype and genotype in multiple regions, followed by full-genome sequencing, was used to identify this strain. Pending vaccine trials in Thailand require knowledge of the presence of such strains in the population, and these recombinants provide valuable reagents for the laboratory evaluation of cross-subtype immunity. Studies are underway to determine whether either recombinant is circulating widely.

HIV Infections↗

PubMed1996

Genotype determination of hepatitis C virus from northern India: identification of a new subtype.

Hepatitis C virus (HCV) shows substantial nucleotide sequence diversity distributed throughout the viral genome, with many variants showing only 68-79% overall sequence homology. This has led to problems in diagnosis of HCV using commercial immunoassays. Based on clustering of homologous sequences, various genotypes and subtypes of HCV have been described from different geographical regions. In the present study, 11 isolates from India were genotyped using sequence comparison for part of the non-structural (NS5) and structural (core) regions. Parts of the genome covering 451 bp (nt 9-459) of the core gene and a 249 bp fragment (nt 7959-8207) of the NS5 gene were reverse transcribed and amplified using nested polymerase chain reaction (RT-PCR). The amplified fragments were cloned and sequenced. The classification into genotypes was done on the basis of phylogenetic analysis. Four isolates showed sequence homology to type 1b. Two of the isolates were classified as type 3a. One isolate was classified as type 3b and the remaining four isolates were found to be variants of type 3 but did not belong to any designated subtype. On the basis of phylogenetic analysis two of the unclassified isolates were put into a new subtype of 3 named as 3g. In one of these variants, parts of a 5'-noncoding (5' NCR; 204 bp), envelope-E1 (435 bp), and NS3 (502 bp) regions were also amplified, cloned, and sequenced. This study demonstrates the type 3 variants including a new subtype (3g) to be the major cause of HCV infection in India.

Amino Acid Sequence↗

PubMed1997

A practical approach to genetic screening for influenza virus variants.

This report describes a quick genetic approach to the screening of influenza virus variants. Multiplex reverse transcription (MRT) and multiplex PCR (MPCR) were used to amplify and differentiate the hemagglutinin (HA) genes of different types and subtypes of influenza viruses. Heteroduplex mobility assay (HMA) was then used to differentiate strains within the same type and subtype. Three primers complementary to the consensus 3' termini of viral genomic RNA segments of human influenza virus types A, B, and C were used in a single MRT reaction to prime the synthesis of cDNA of all the viral genome segments. The cDNA was then amplified in an MPCR containing primers for the HA genes of the H1 and H3 subtypes of type A, the HA gene of type B, and the counterpart of type C virus. Amplicons of the different types and subtypes differ in size, thus allowing typing and subtyping. The regions amplified cover most of the HA1 portion of the HA genes and therefore amplicons of variants identified by the described HMA can be sequenced directly. In the HMA, the amplicon of an individual strain was mixed with that of a reference strain and heteroduplexes derived from mismatches migrated more slowly than homoduplexes of the same size in electrophoresis, with the mobility shift pattern indicating the divergence of amplicons. The whole process from viral RNA extraction to HMA can be completed within 2 days and thus provides a quick screening before further analysis by hemagglutination inhibition testing and sequencing. In addition, all segments of the viral genome can be amplified from a single MRT reaction, which can yield valuable sources of products for future genetic analyses. This method should facilitate genetic screening and characterization of influenza virus variants.

Antigenic Variation↗

PubMed2025

Exploring prognostic genes in the immune microenvironment of acute myeloid leukemia via weighted gene co-expression network analysis.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous blood cancer that arises from transformed myeloid precursor cells in a compromised bone marrow microenvironment. This environment is essential for AML initiation, progression, and relapse. Alongside oncogenic changes in hematopoietic cells, immunological dysregulation also contributes to leukemogenesis. The present study is aimed to identify prognostic genes in stromal and immune cells associated with AML using the weighted gene co-expression network analysis (WGCNA). METHODS: Gene expression profiles were retrieved from The Cancer Genome Atlas database, and immune and stromal cell scores were calculated using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) method. These scores helped identify differentially expressed genes (DEGs), which were then used to create gene clusters through WGCNA. To explore the functions of genes linked to AML subtypes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. A protein-protein interaction network was developed to identify hub genes. The top 18 hub genes were identified using the cytoHubba plug-in in Cytoscape software, and survival analysis was conducted with the Gene Expression Profiling Interactive Analysis 2 online tool. RESULTS: A total of 1097 DEGs were identified, with 601 being upregulated and 496 downregulated. WGCNA analysis indicated that the gray module, comprising 165 genes, had the strongest association with AML subtypes (Cor > 0.3; P < .05). Gene Ontology enrichment analysis demonstrated that the 18 identified hub genes were predominantly associated with neutrophil activation, immune response, secretory granule membrane, and pattern recognition receptor activity. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the DEGs were mainly involved in pathways related to phagosome, lysosome, tuberculosis, leishmaniasis, and neutrophil extracellular trap formation. Kaplan-Meier survival analysis of the top 18 hub genes indicated that ITGAM, IL10, and CD163 were significantly correlated with survival outcomes in AML. CONCLUSION: Key stromal and immune-related genes influencing AML patient outcomes were identified, highlighting their potential as therapeutic targets. These discoveries provide deeper insights into the molecular mechanisms driving AML pathogenesis and subtype differentiation.

Leukemia, Myeloid, Acute↗

PubMed1997

Human immunodeficiency virus type 1 intersubtype (B/E) recombination in a superinfected chimpanzee.

Genetic characterization of a large number of human immunodeficiency virus type 1 (HIV-1) isolates indicates that at least 10% of all strains have mosaic genomes generated by recombination between viruses of the same or different subtypes or clades. What is not known, however, is the time between infection with the first and second HIV-1 strains as well as the time between infection with the second strain and the recombinational event. After 32 months of infection with HIV-1(LAI(IIIB)), a chimpanzee was inoculated intravenously and became infected with a subtype E strain, HIV-1(90CR402). With PCR amplification, DNA heteroduplex analysis, and DNA sequencing, both parental strains and two distinct recombinant proviruses were found in genomic DNA from lymph node tissue obtained 24 weeks after exposure to HIV-1(90CR402). These results show (i) that antiviral immune responses established by long-term infection with an HIV-1 subtype B strain did not prevent infection by a subtype E strain and (ii) that both strains actively replicated and produced sufficient quantities of virus to coinfect the same cell(s), resulting in recombinant viruses.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Genomic alterations identified by array comparative genomic hybridization as prognostic markers in tamoxifen-treated estrogen receptor-positive breast cancer.

BACKGROUND: A considerable proportion of estrogen receptor (ER)-positive breast cancer recurs despite tamoxifen treatment, which is a serious problem commonly encountered in clinical practice. We tried to find novel prognostic markers in this subtype of breast cancer. METHODS: We performed array comparative genomic hybridization (CGH) with 1,440 human bacterial artificial chromosome (BAC) clones to assess copy number changes in 28 fresh-frozen ER-positive breast cancer tissues. All of the patients included had received at least 1 year of tamoxifen treatment. Nine patients had distant recurrence within 5 years (Recurrence group) of diagnosis and 19 patients were alive without disease at least 5 years after diagnosis (Non-recurrence group). RESULTS: Potential prognostic variables were comparable between the two groups. In an unsupervised clustering analysis, samples from each group were well separated. The most common regions of gain in all samples were 1q32.1, 17q23.3, 8q24.11, 17q12-q21.1, and 8p11.21, and the most common regions of loss were 6q14.1-q16.3, 11q21-q24.3, and 13q13.2-q14.3, as called by CGH-Explorer software. The average frequency of copy number changes was similar between the two groups. The most significant chromosomal alterations found more often in the Recurrence group using two different statistical methods were loss of 11p15.5-p15.4, 1p36.33, 11q13.1, and 11p11.2 (adjusted p values < 0.001). In subgroup analysis according to lymph node status, loss of 11p15 and 1p36 were found more often in Recurrence group with borderline significance within the lymph node positive patients (adjusted p = 0.052). CONCLUSION: Our array CGH analysis with BAC clones could detect various genomic alterations in ER-positive breast cancers, and Recurrence group samples showed a significantly different pattern of DNA copy number changes than did Non-recurrence group samples.

Adult↗

PubMed2001

Diverse BF recombinants have spread widely since the introduction of HIV-1 into South America.

OBJECTIVE: To describe the genetic diversity of HIV-1 in South America by full genome sequencing and analysis. METHODS: Purified peripheral blood mononuclear cell DNA from HIV-infected individuals in Argentina, Uruguay and Bolivia was used to amplify full HIV-1 genomes. These were sequenced using the ABI 3100 automated sequencer and phylogenetically analysed. RESULTS: Twenty-one HIV-1 strains from three South American countries, 17 of which were pre-screened by envelope heteroduplex mobility assay (HMA), were studied. Ten out of 10 HMA subtype F and four out of seven HMA subtype B strains were actually BF recombinants upon full genome analysis. Two BF recombinants from Argentina and two from Uruguay had the same structure, representing a new circulating recombinant form termed CRF12_BF(ARMA159). Twelve other BF recombinants had structures related to CRF12 but with additional segments of subtype B; each was unique. BF recombinants were temporally and geographically widespread, found as early as 1986-1987 in vertically infected Argentinian children and in Argentina, Uruguay, and Bolivia.

Adult↗