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PubMed2026

Machine learning-enabled multi-omics discovery of prognostic biomarkers and signaling targets in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains difficult to subtype using single omics layers. We conducted an exploratory investigation integrating reverse-phase protein array (RPPA) and DNA methylation data from the cancer genome atlas (TCGA)- pancreatic adenocarcinoma (PAAD) to assess the feasibility of multi-omics subtyping, alongside a supervised machine learning analysis of a small gene expression omnibus (GEO) transcriptomic cohort (n = 26) to identify candidate diagnostic genes. RPPA-based K-means clustering suggested a weak, possible two-subtype structure (silhouette ≈ 0.16) that remained unassociated with overall survival (log-rank p = 0.113) and lacked independent prognostic value. An independently performed similarity network fusion (SNF) analysis integrating RPPA and methylation data showed low concordance with RPPA-derived subtypes (Adjusted Rand Index (ARI) = 0.014), indicating limited convergence between molecular modalities. Supervised machine learning analysis of the GEO cohort using a fully nested leave-one-out cross-validation pipeline achieved a mean (area under the curve) AUC of 0.896 across four classifiers and identified four-fold-stable candidate genes (ESCO2, COL17A1, BCL2L14, and SOWAHB). However, this gene panel demonstrated limited external validity across two independent PDAC cohorts (log-rank p = 0.438 for both GSE62452 and GSE28735), indicating limited generalizability despite robust internal performance. Collectively, these findings provide limited evidence for a robust, prognostically significant multi-omics subtype or a validated diagnostic gene signature; instead, this study serves as a hypothesis-generating resource and highlights the importance of rigorous cross-validation and independent external validation in small-sample transcriptomic biomarker discovery.

Humans↗

PubMed1980

Cloning of human papilloma virus genomic DNAs and analysis of homologous polynucleotide sequences.

The complete DNA genomes of four distinct human papilloma viruses (human papilloma virus subtype 1a [HPV-1a], HPV-1b, HPV-2a, and HPV-4) were molecularly cloned in Escherichia coli, using the certified plasmid vector pBR322. The restriction endonuclease patterns of the cloned HPV-1a and HPV-1b DNAs were similar to those already published for uncloned DNAs. Physical maps were constructed for HPV-2a DNA and HPV-4 DNA, since these viral DNAs had not been previously mapped. By using the cloned DNAs, the genomes of HPV-1a, HPV-2a, and HPV-4 were analyzed for nucleotide sequence homology. Under standard hybridization conditions (Tm = --28 degrees C), no homology was detectable among the genomes of these papilloma viruses, in agreement with previous reports. However, under less stringent conditions (i.e., Tm = --50 degrees C), stable DNA hybrids could be detected between these viral DNAs, indicating homologous segments in the genomes with approximately 30% base mismatch. By using specific DNA fragments immobilized on nitrocellulose filters, these regions of homology were mapped. Hybridization experiments between radiolabeled bovine papilloma virus type 1 (BPV-1) DNA and the unlabeled HPV-1a, HPV-2a, or HPV-4 DNA restriction fragments under low-stringency conditions indicated that the regions of homology among the HPV DNAs are also conserved in the BPV-1 genome with approximately the same degree of base mismatch.

Base Sequence↗

PubMed2000

Subtype-specific sequence variation of the HIV type 1 long terminal repeat and primer-binding site.

We studied sequence differences in regulatory elements of the long terminal repeat (LTR) and primer-binding site (PBS) among various human immunodeficiency virus type 1 (HIV-1) subtypes. Phylogenetic sequence analysis of a fragment of 729 base pairs (bp) covering the Gag-coding region for half of p24 and all of p17 revealed the gag subtype of all 60 viruses included in the study: A (n = 20), B (n = 12), C (n = 7), D (n = 10), E (n = 3), F (n = 4), G (n = 3), and H (n = 1). The subtype was also determined by analysis of a 689-bp fragment comprising the LTR and the PBS motif. Comparison of the LTR versus gag sequences showed a mosaic genome for seven isolates. After analysis of all sequences, we could describe subtype-specific differences in sequences encompassing the regulatory elements of the LTR and the PBS motif.

Base Sequence↗

PubMed2005

HIV-1 intra-subtype superinfection rates: estimates using a structured coalescent with recombination.

Because recombination between a pair of viral genomes can occur only when both viruses are present in the same host, genealogical evidence of recombination is influenced by the rate of viral migration between infected hosts. If superinfection is rare, then recombining viral genomes will usually be more closely related to each other than to viral genomes present in other hosts and the impact of recombination on the genealogy of a sample of viruses from different hosts may be weak. We used this relationship to estimate the relative rate of intra-subtype HIV-1 superinfection in six urban populations. Comparisons of the population recombination rates estimated from the HIV-1 sequence data with population recombination rates estimated for sets of sequences simulated using a structured coalescent process suggest that intra-subtype superinfection rates in all but one of these populations may be as high as 15% of the corresponding infection rate. However, we caution that these estimates might be upwardly biased if variation in contact and mixing rates between infected hosts causes viral lineages to be concentrated in groups with higher than average superinfection rates.

Evolution, Molecular↗

PubMed2026

The machine-learning classifier ALLCatchR2 identifies 20 T-ALL subtypes across cohorts and age groups.

T-cell acute lymphoblastic leukemia (T-ALL) comprises molecularly diverse subtypes, but robust cross-cohort validations and operational gene-expression definitions are lacking. To establish a gene-expression-anchored framework for T-ALL subtyping, we aggregated 2314 transcriptomes (15 cohorts, age: 0.8-90.8 years). An extended unsupervised approach defined 17 main clusters and 3 subclusters in samples with high blast fractions. Supervised analyses added an overarching immature T-ALL (early T cell precursor [ETP]-like) definition and resolved the LMO2 γδ-like subtype. All clusters contained samples from at least two cohorts. Characteristic genomic driver enrichments were consistent across cohorts, while gene-expression clusters did not correspond exclusively to single driver events but also reflected developmental origins. A machine-learning classifier based on ALLCatchR, our B-cell acute lymphoblastic leukemia (B-ALL) classifier, identified these 20 transcriptomic subtypes and the immature T-ALL (ETP-like) signature with 0.995-1.0 accuracy in a validation set (n = 203). Testing the classifier on a second hold-out data set (n = 265 samples) showed that 92.7% of predictions matched with corresponding driver alterations. Across all samples, 83.2% of cases received high-confidence predictions, 7.3% candidate predictions, and 9.5% remained unclassified, largely because of low blast fractions. We identified a novel gene-expression cluster markedly enriched (P < 0.001) for clonal hematopoiesis mutations (IDH2 R140Q, DNMT3A) and a stem-/progenitor cell-like gene expression. This novel clonal hematopoiesis-related T-ALL subtype was observed in six cohorts and accounted for 8.9% of adults and 39.5% of patients aged >50 years. We extended ALLCatchR into ALLCatchR2, a free R package that now enables B-/T-lineage separation, gene-expression subtyping, blast estimation, and developmental annotation to harmonize T-ALL classification across studies and clinical contexts.

Journal Article↗

PubMed1993

BRS-3: a novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells.

The bombesin (BN)-like peptides mediate a diverse spectrum of biological activities and have been implicated as autocrine growth factors in the pathogenesis and progression of some human small cell lung carcinoma tumors. Previously, two mammalian BN-like peptide receptor subtypes, gastrin-releasing peptide receptor and neuromedin-B receptor, have been cloned and characterized. In this study, we have isolated and characterized human genomic and complementary DNA (cDNA) clones encoding a new BN-like peptide receptor subtype, BN receptor subtype 3 (BRS-3). Expression of BRS-3 cDNA in Xenopus oocytes encodes a functional receptor that is specifically activated by BN-like peptides. Chromosome mapping studies indicate that the BRS-3 gene is located on human chromosome X. BRS-3 mRNA expression in rat tissues is limited to secondary spermatocytes in testis. In contrast, BRS-3 mRNA is widely expressed in a panel of human cell lines from all histological types of lung carcinoma. These results suggest a role for BN-like peptides and their receptors in mammalian reproductive physiology and also indicate that BRS-3 could serve as a potential therapeutic target for human lung carcinoma.

Amino Acid Sequence↗

PubMed1985

Multiple sites of recombination within the RNA genome of foot-and-mouth disease virus.

Recombinant foot-and-mouth disease viruses were isolated from cells infected with a mixture of temperature-sensitive (ts) mutants belonging to different subtype strains. In order to select for recombination events in many different regions of the genome, crosses were performed between various pairs of mutants, with ts mutations in different regions of the genome. ts+ progeny were analysed by electrofocusing virus-induced proteins and RNase T1 fingerprinting of their RNA. All but 5 out of 43 independent isolates, from nine crosses, proved to have recombinant RNA genomes. Maps of these genomes, based on a knowledge of the locations of the unique oligonucleotides, were constructed. Most could be interpreted as being the products of single genetic cross-overs, although three recombinants were formed by two cross-overs each. Cross-overs in at least twelve distinct regions of the genome were identified. This evidence of a large number of recombination sites suggests that RNA recombination in picornaviruses is a general, as opposed to a site-specific, phenomenon.

Aphthovirus↗

PubMed1999

Subtype G and multiple forms of A/G intersubtype recombinant human immunodeficiency virus type 1 in Nigeria.

Multiple human immunodeficiency virus type 1 (HIV-1) genetic subtypes, intersubtype recombinants, and group O have been found in west central Africa. In Nigeria, where HIV-1 prevalence is rising rapidly, characterization of HIV-1 strains has been limited. Each of three full-length genome sequences acquired to date shows evidence of recombination: two are largely subtype G with subtype A segments in the midgenome accessory region; the third, IbNG, is subtype G with the long terminal repeats and two segments of pol from subtype A. In this study, peripheral blood mononuclear cells obtained in 1994-1995 from 10 patients hospitalized in northeastern Nigeria were evaluated by sequencing of the complete envelope and, from 7 patients, a portion of gag. Four patients harbored subtype G viruses and six patients had recombinant viruses. Two had strains sharing the A/G recombinant structure of IbNG. Two had a previously undescribed recombinant, mostly subtype A, whose carboxyl-terminal gp41 could not be classified. An A/G recombinant different from IbNG but similar to CA1, a Cameroonian strain, was found in one patient. The remaining patient had a strain that was otherwise subtype G but shared an unclassified carboxyl-terminal gp41 segment with the CA1-like strains. Other subtypes and group O were not found.

Base Sequence↗

PubMed2006

Genetic variability of bovine viral diarrhoea virus subtypes at 3'-nontranslated region.

Ten isolates belonging to different BVDV-1 subtypes and three BVDV-2 isolates were studied in 3'-nontranslated region (3'-NTR) by sequencing of PCR products and comparative computer-assisted nucleotide sequence analysis. The alignment of nucleotide sequences revealed that all BVDV-1 isolates except BVDV-1a isolates represented by NADL strain were characterised with a deletion of 38 nucleotides in the variable region located after the stop codon. For all BVDV-1 subtypes, a constant region at the end of viral genome was highly conserved. The variable and constant regions with no significant insertions or deletions were also identified in BVDV-2 isolates. The poly AT reach region was situated at different locations in both pestiviruses.

3' Untranslated Regions↗

PubMed1995

Rapid genotyping of hepatitis C virus isolates by dideoxy fingerprinting.

A number of distinct hepatitis C virus (HCV) types and subtypes have been identified by DNA sequencing of multiple genome regions. It has been postulated that these might also reflect phenotypic differences in the nature of HCV infection. Recent evidence suggests a relationship between HCV genotype and alpha-interferon response in patients with chronic hepatitis C. A simplified method of genotyping in comparison to direct DNA sequencing was investigated with the intention of providing a rapid, less labour-intensive method for routine genotyping. HCV RNA was extracted from serum by a modified guanidinium/acid-phenol extraction and peripheral blood lymphocytes using RNAzol B (Cinna-Biotecx). The RNA was reverse transcribed and a 287 bp segment of the 5' non-coding region (5' NCR) amplified using a nested-PCR reaction. PCR products were purified using Qiaquick spin columns. Products were directly sequenced by cycle sequencing. Dideoxy termination analysis was carried out by cyclic extension of a 33P-labelled primer by Tth polymerase with termination by dideoxy thiamine (ddT) or cytosine (ddC). Reaction products were analysed by electrophoresis on denaturing 7 M urea/6% acrylamide gels followed by autoradiography. Computer aided sequence analysis indicated that conserved 5' NCR sequence variation alone was sufficient to identify HCV types 1a, 1b, 2a, 2b, 3 and 4. Dideoxy fingerprinting improved greatly the efficiency of genotyping with an approximate four-fold increase in throughput. In addition, the results were very easily analysed although it was essential to run appropriate controls for each genotype. Reactions incorporating ddT distinguished types 1, 2a, 2b, 3 (provisionally 1a & 1b); a ddC reaction confirmed 1a and 1b typing.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed1996

Heteroduplex mobility assay for subtyping HIV-1: improved methodology and comparison with phylogenetic analysis of sequence data.

The feasibility of using DNA heteroduplex mobility analysis (HMA) as a rapid and reproducible method for routine subtyping HIV-1 in clinical specimens was examined by comparison with subtype determination by sequencing in both the gag and env genes. The heteroduplexes formed were examined by conventional polyacrylamide gel electrophoresis (PAGE) and also by electrophoresis in the Pharmacia PhastSystem. The significance of the HMA results was determined by the Kruskal-Wallis test, a non-parametric one way analysis of variance. It was possible to obtain an HMA profile rapidly (1-2 days) using fast PCR conditions and the PhastSystem. The HMA bands were generally sharper and more satisfactory on the Phast gels than on conventional polyacrylamide gels and the use of Phast gels was an improvement over conventional PAGE. Non-B subtype viruses could be distinguished from B subtypes, but it was more difficult to distinguish between the non-B subtypes and to assign a subtype to them. Thus, HMA can be adapted to offer a rapid screening method for HIV-1 subtyping, but sequencing is still necessary to assign a definitive subtype. This reflects the empirical nature of the subtype definitions and the quasispecies nature of the HIV genome population.

DNA, Viral↗

PubMed2004

Simultaneous detection of enteric viruses by multiplex real-time RT-PCR.

A multiplex real-time RT-PCR protocol for the simultaneous detection of noroviruses ("Norwalk-like viruses") of genogroups I and II, human astroviruses and enteroviruses is described. The protocol was developed and evaluated using the LightCycler and corresponding SYBR Green reagents. New primers were designed within conserved genome regions to optimize the detection range of virus subtypes of each genus. To enable the development of a multiplex PCR assay within one tube (capillary), similar mastermix- and cycling-conditions were respected for each individual primer system. Subsequent melting curve analysis allowed the determination of possible dual-contaminations of entero- and noro- or astroviruses by the formation of dual peaks. Special care was taken to minimize the loss of sensitivity, since the detection of small viral contaminations is a crucial parameter especially for food analysis. The multiplex assay was compared successfully to the single SYBR Green assay, and revealed to be at least 10 times more sensitive than the one obtained with an endpoint PCR thermocycler protocol published previously.

Benzothiazoles↗

PubMed2005

Sample size calculation for multiple testing in microarray data analysis.

Microarray technology is rapidly emerging for genome-wide screening of differentially expressed genes between clinical subtypes or different conditions of human diseases. Traditional statistical testing approaches, such as the two-sample t-test or Wilcoxon test, are frequently used for evaluating statistical significance of informative expressions but require adjustment for large-scale multiplicity. Due to its simplicity, Bonferroni adjustment has been widely used to circumvent this problem. It is well known, however, that the standard Bonferroni test is often very conservative. In the present paper, we compare three multiple testing procedures in the microarray context: the original Bonferroni method, a Bonferroni-type improved single-step method and a step-down method. The latter two methods are based on nonparametric resampling, by which the null distribution can be derived with the dependency structure among gene expressions preserved and the family-wise error rate accurately controlled at the desired level. We also present a sample size calculation method for designing microarray studies. Through simulations and data analyses, we find that the proposed methods for testing and sample size calculation are computationally fast and control error and power precisely.

Computer Simulation↗

PubMed1993

Chromosomal assignment of human and rat hypertension candidate genes: type 1 angiotensin II receptor genes and the SA gene.

OBJECTIVE: The chromosomal location of candidate genes for a disease, especially if the disease is multifactorial, is an important datum. The objective of the present study was to determine the chromosomal location of candidate hypertensinogenic genes, both in humans and in the rat, a species widely used for animal models of human hypertension. The type 1 angiotensin II receptor (AT1) genes are obvious hypertension candidate genes, whereas the SA gene has recently been shown to cosegregate with hypertension in the rat. DESIGN: The chromosomal location of the relevant genes was determined using somatic cell hybrids segregating either human chromosomes or rat chromosomes. The presence of the human or rat genes was determined by the Southern blot method, using rat probes. RESULTS: A single AT1 gene (AT1) was detected in the human genome, and was assigned to chromosome 3, whereas two non-syntenic genes were detected in the rat genome, corresponding to the previously identified A and B subtypes. They were assigned to the rat chromosome 17 (At1a) and 2 (AT1b). The Sa gene was assigned to human chromosome 16 and rat chromosome 1, disclosing a new synteny group retained on rat chromosome 1 and human chromosome 16. CONCLUSIONS: These chromosomal assignments should be useful for linkage analyses of genes controlling blood pressure. The genes that we studied, and the chromosomes that we identified, deserve special attention in such linkage analyses.

Angiotensin II↗

PubMed2005

[Molecular epidemiology of mechicillin-resistant Staphylococcus aureus (MRSA) by pulsed-field gel electrophoresis].

A total of 103 methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients and 78 MRSA from hospital workers during the years 1990 to 1994, and 52 MRSA from patients in year 2000, in one hospital at Wakayama Prefecture, were typed by pulsed-field gel electrophoresis (PFGE) profiles. MRSA isolates were grouped into 20 genomic types. These types were further divided into 57 subtypes. The type 1 was dominant among patients, and closely related type 1 strains were spread during 1990-1993. In contrast, the type 2 was dominant among medical workers in the same period. In 2000, the type 2 and 4 strains increased, and the diversity and complication of types appeared. The common types between the patients and medical workers were only type 1 to 3. Some strains isolated from both during the same period were shown to have the same types. Others were shown to be patient-specific types. These results suggest that there are complicated transmissions of MRSA in the hospital, i.e., the endogenous infection, patient-patient cross infection and medical worker-patient cross infection.

Bacterial Typing Techniques↗

PubMed2004

Characterization of a highly evolved vaccine-derived poliovirus type 3 isolated from sewage in Estonia.

Two types of vaccine-derived polioviruses have been recently designated to emphasize the different origins of the evolved viruses: circulating vaccine-derived polioviruses (cVDPV) associated with outbreaks of paralytic disease and strains isolated from chronically infected immunodeficient individuals (iVDPV). We describe here a type 3 VDPV (PV3/EST/02/E252; later E252) isolated from sewage collected in Tallinn, Estonia, in October 2002. Due to aberrant properties in subtyping, the virus was subjected to detailed characterization. Partial genomic sequencing suggested that the closest relative was the oral vaccine strain PV3/Sabin, but the two virus strains shared only 86.7% of the 900 nucleotides (nt) coding for the capsid protein VP1. Phylogenetic analysis of the nearly complete genome [nt 19 to poly(A)] revealed multiple nucleotide substitutions throughout the genome and a possible Sabin 3/Sabin 1-recombination junction site in the 2C coding region. A calculation based on the estimated mutation frequency of the P1 region of polioviruses suggested that the E252 virus might have replicated in one or more individuals for approximately 10 years. No persons chronically excreting poliovirus are known in Estonia. Amino acid substitutions were seen in all known antigenic sites, which was consistent with the observed aberrant antigenic properties of the virus demonstrated by both monoclonal antibodies and human sera from vaccinated children. In spite of the apparent transmission potential, no evidence was obtained for circulation of the virus in the Estonian population.

Amino Acid Sequence↗

PubMed2001

A dominant gene for developmental dyslexia on chromosome 3.

Developmental dyslexia is a neurofunctional disorder characterised by an unexpected difficulty in learning to read and write despite adequate intelligence, motivation, and education. Previous studies have suggested mostly quantitative susceptibility loci for dyslexia on chromosomes 1, 2, 6, and 15, but no genes have been identified yet. We studied a large pedigree, ascertained from 140 families considered, segregating pronounced dyslexia in an autosomal dominant fashion. Affected status and the subtype of dyslexia were determined by neuropsychological tests. A genome scan with 320 markers showed a novel dominant locus linked to dyslexia in the pericentromeric region of chromosome 3 with a multipoint lod score of 3.84. Nineteen out of 21 affected pedigree members shared this region identical by descent (corrected p<0.001). Previously implicated genomic regions showed no evidence for linkage. Sequencing of two positional candidate genes, 5HT1F and DRD3, did not support their role in dyslexia. The new locus on chromosome 3 is associated with deficits in all three essential components involved in the reading process, namely phonological awareness, rapid naming, and verbal short term memory.

Adolescent↗

PubMed1997

Detection of influenza virus RNA in peripheral blood mononuclear cells of influenza patients.

Gastroenteritis, arthralgaia and myalgia are frequently associated with influenza virus infections in humans. One explantation for these symptoms may be extrarespiratory transmission of virus by peripheral blood mononuclear cells (PBMC). We tried to detect genomic viral RNA of the nucleoprotein (NP) and H3 subtype hemagglutinin (HA) genes by the method of RT-PCR in PBMC of 18 children aged 1-14 who suffered from an influenza outbreak in the Kansai district of Japan between December 1992 and February 1993. Three of the 18 samples were RT-PCR positive. The NP gene sequence observed in one patient's PBMC was identical to that obtained from his throat swab fluid. The HA gene sequences observed in the two other PBMC differed from those of RT-PCR-amplified DNA from throat swabs by an order of 3-9 nucleotides. We believe these results suggest the presence of a PBMC-associated virus.

Adolescent↗