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PubMed2025

Pharmacogenomics-based subtype decoded implications for risk stratification and immunotherapy in pancreatic adenocarcinoma.

BACKGROUND: With fatal malignant peculiarities and poor survival rate, outcomes of pancreatic adenocarcinoma (PAAD) were frustrated by non-response and even resistance to therapy due to heterogeneity across clinical patients. Nevertheless, pharmacogenomics has been developed for individualized-treatment and still maintains obscure in PAAD. METHODS: A total of 964 samples from 10 independent multi-center cohorts were enrolled in our study. With drug response data from the profiling of relative inhibition simultaneously in mixtures (PRISM) and genomics of drug sensitivity in cancer (GDSC) databases, we established and validated multidimensionally three pharmacogenomics-classified subtypes using non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithms, separately. The heterogenous biological characteristics and precision medicine strategies among subtypes were further investigated. RESULTS: Three pharmacogenomics-classified subtypes after stable and reproducible validation, distinguished in six aspects of prognosis, biological peculiarities, immune landscapes, genomic variations, immunotherapy and individualized management strategies. Subtype 2 was close to immunocompetent phenotype and projected to immunotherapy; Subtype 3 held most favorable outcomes and metabolic pathways distinctively, promising to be treated with first-line agents. Subtype 1 with worst prognosis, was anticipated to chromosome instability (CIN) phenotype and resistant to chemotherapeutic agents. In addition, ITGB6 contributed to subtype 1 resistance to 5-fluorouracil, and knockdown of ITGB6 enhanced sensitivity to 5-fluorouracil in in vitro experiments. Ultimately, appropriate clinical stratified treatments were assigned to corresponding subtypes according to pharmacogenomic transcripts. Some limitations were not taken into account, thus needs to be supported by more research. CONCLUSION: A span-new molecular subtype exploited for PAAD uncovered an insight into precise medication on ground of pharmacogenomics, and highly refined multiple clinical management strategies for specific patients.

Humans↗

PubMed2002

Novel evolutionary analyses of full-length HIV type 1 subtype C molecular clones from Cape Town, South Africa.

Understanding the origin, distribution, and evolving dominance of HIV-1 subtype C strains is an important component in the design and evaluation of a globally effective AIDS vaccine. To better understand subtype C viruses, we constructed complete molecular clones of primary, CCR-5-using isolates from South Africa and analyzed the molecular phylogenies of these clones using best fitting evolutionary substitution models. Analyses were performed on three full-length sequences, and on the individual genes. All clones were nonrecombinant, and although two of three had open reading frames and intact splice sites, they were not infectious. At the genomic level, the models demonstrated the increasing variability of subtype C in South Africa. At the subgenomic level, they revealed marked differences in the evolutionary patterns of individual genes, a finding that suggests that the genes are under different selective pressures and constraints. These data underscore the dynamic nature of the subtype C epidemic and emphasize the need for continuous monitoring of local strains.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Co-expression of Epstein-Barr virus latent membrane protein and vimentin in "aggressive" histological subtypes of Hodgkin's disease.

The presence of Epstein-Barr virus (EBV) genome in Hodgkin's and Reed-Sternberg (HRS) cells, as detected using in situ hybridization (ISH) with biotinylated BamHI "V" probes, along with the expression of EBV-encoded latent membrane protein (LMP) and vimentin was examined in paraffin-embedded sections of 39 immunomorphologically characterized cases of Hodgkin's disease (HD). ISH demonstrated EBV in HRS cells in 15 of 39 cases, whereas LMP expression was detected in 11 of 39 cases, only in the presence of EBV genome detection. With the exception of 1 case, in which HRS cells expressed B-cell-associated antigens, the LMP-positive cases included specimens in which HRS cells were of non-B, non-T phenotype. LMP expression showed a stronger association with lymphocyte depletion (LD) (3/3) and mixed cellularity (MC) (6/11) than with lymphocyte predominance (0/5) or nodular sclerosis (2/20) subtypes. Vimentin expression on HRS cells was found in all the LMP-expressing cases and only in a fraction (13/28) of LMP-negative cases. This study supports the view that HD represents a heterogeneous group of diseases also in terms of EBV association, LMP expression being strongly related to the "aggressive" LD and MC histological subtypes. In light of the supposed interactions between vimentin and LMP, their co-expression on HRS cells, as detected in this study, provides further evidence for a significant role of EBV in the development of a proportion of HD cases.

Antigens, CD↗

PubMed2002

Identification of a new circulating recombinant form of HIV type 1, CRF11-cpx, involving subtypes A, G, J, and CRF01-AE, in Central Africa.

In this study, we characterized three full-length genome sequences with a similar mosaic structure from epidemiologically unlinked individuals from Cameroon (97CM-MP818) and the Central African Republic (99CF-MP1298 and 99CF-MP1307). Phylogenetic and recombinant analysis confirmed that the three strains had a similar complex recombinant genome, which we can designate now as CRF11-cpx. This new CRF was composed of successive fragments of subtype A, G, J, and CRF01-AE. The previously reported GR17 virus from a Greek patient infected in the Democratic Republic of Congo (DRC) has a similar structure and should be considered as the prototype strain of CRF11-cpx. This new CRF circulates in Cameroon, Central African Republic, Gabon, and DRC, although the exact prevalences remain to be determined.

Base Sequence↗

PubMed2026

IGH::FENDRR and specific KRAS mutations define a novel B-ALL molecular subtype with poor chemotherapy response.

Large-scale sequencing efforts have defined up to 27 diagnostic subtypes in B-cell precursor acute lymphoblastic leukemia (B-ALL), leaving few samples unclassified. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection, enabling identification of novel subtypes. We analyzed 4857 patients with B-ALL from 3 cohorts and identified a group of 20 patients (age, 18-66 years; median, 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n = 17/20), KRAS p.A146T/V/P mutations (n = 17/20 vs n = 86/4857; P< .001), and distinct DNA methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 (FOXF1/FENDRR) as well as JAK/STAT and RAS/MAPK signaling signatures. A gene expression machine learning classifier accurately identified FOXF1/FENDRR cases in 2 independent cohorts. Patients treated according to German Multicenter Study Group for Adult ALL (GMALL)/Group for Research in Adult ALL (GRAALL) protocols showed very poor chemotherapy response with 8 of 13 exhibiting induction failure or minimal residual disease (MRD) ≥10-3 and 8 of 12 remaining MRD positive after first consolidation/salvage. Intensification including blinatumomab (n = 10) and/or allogeneic stem cell transplantation (n = 12) resulted in ongoing molecular remission in 13 of 16 patients. FOXF1/FENDRR represents a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.

Humans↗

PubMed2001

Charting the map of life.

Scientists expect that mapping the human genome will lead to a host of innovations in biology and research. For example, it may become possible to use DNA microarrays to accurately diagnose cancer and infectious disease subtypes and to predict clinical outcomes. Scientists might also use the genome to look at the interactions of the environment, genetic makeup, and toxic exposures, including the ability of certain beneficial genes to detoxify the body and resist disease. But despite the great potential of the field of genomics, scientists caution that public expectations need to be tempered by reality. People are as much a product of their environment as they are of their genes, say experts, and to suggest that genetics is the sole determinant that defines humans as individuals stretches the science beyond the current data.

Animals↗

PubMed2006

Second generation subtyping: a proposed PulseNet protocol for multiple-locus variable-number tandem repeat analysis of Shiga toxin-producing Escherichia coli O157 (STEC O157).

Most bacterial genomes contain tandem duplications of short DNA sequences, termed "variable-number tandem repeats" (VNTR). A subtyping method targeting these repeats, multiple-locus VNTR analysis (MLVA), has emerged as a powerful tool for characterization of clonal organisms such as Shiga toxin-producing Escherichia coli O157 (STEC O157). We modified and optimized a recently published MLVA scheme targeting 29 polymorphic VNTR regions of STEC O157 to render it suitable for routine use by public health laboratories that participate in PulseNet, the national and international molecular subtyping network for foodborne disease surveillance. Nine VNTR loci were included in the final protocol. They were amplified in three PCR reactions, after which the PCR products were sized using capillary electrophoresis. Two hundred geographically diverse, sporadic and outbreak- related STEC O157 isolates were characterized by MLVA and the results were compared with data obtained by pulsed-field gel electrophoresis (PFGE) using XbaI macrorestriction of genomic DNA. A total of 139 unique XbaI PFGE patterns and 162 MLVA types were identified. A subset of 100 isolates characterized by both XbaI and BlnI macrorestriction had 62 unique PFGE and MLVA types. Although the clustering of isolates by the two subtyping systems was generally in agreement, some discrepancies were observed. Importantly, MLVA was able to discriminate among some epidemiologically unrelated isolates which were indistinguishable by PFGE. However, among strains from three of the eight outbreaks included in the study, two single locus MLVA variants and one double locus variant were detected among epidemiologically implicated isolates that were indistinguishable by PFGE. Conversely, in three other outbreaks, isolates that were indistinguishable by MLVA displayed multiple PFGE types. An additional more extensive multi-laboratory validation of the MLVA protocol is in progress in order to address critical issues such as establishing epidemiologically relevant interpretation guidelines for the MLVA data.

Base Sequence↗

PubMed1999

Inhibition of histone deacetylation augments dihydrotestosterone induction of androgen receptor levels: an explanation for trichostatin A effects on androgen-induced chromatin remodeling and transcription of the mouse mammary tumor virus promoter.

The integrated mouse mammary tumor virus (MMTV) promoter has provided an excellent model system with which to study the impact of steroid hormones on transcriptional activation in the context of a defined chromatin structure. The hormone response element (HRE) of this promoter is positioned on a phased nucleosome which becomes remodeled in response to steroids. One possible mechanism of chromatin remodeling by steroid receptors could involve recruitment of coactivators which alter the histone acetylation status of the HRE nucleosome. To examine how the androgen receptor (AR) influences transcription and chromatin remodeling and to assess whether changes in histone acetylation are involved in these effects, we determined whether the specific histone deacetylase inhibitor trichostatin A (TSA) influenced basal- and androgen-mediated transcriptional activation of the integrated MMTV promoter in the mouse L-cell fibroblast cell line 29+. These cells harbor the MMTV promoter integrated in the genome and express only one steroid hormone receptor subtype, i.e., the AR. Surprisingly, we found that treatment of the cells with TSA alone had virtually no effect on transcription and chromatin remodeling of the MMTV promoter nor on AR levels. However, pretreatment with TSA augmented the DHT effects on all three parameters. These results suggest that histone acetylation changes at the MMTV B nucleosome per se are not alone sufficient to induce chromatin remodeling and subsequent induction of MMTV transcription. Rather, the histone deacetylase inhibitor TSA exerts a portion of its effect on MMTV chromatin remodeling and transcriptional activation indirectly through increases in AR levels.

Acetylation↗

PubMed2000

Genetic diversity of hantaviruses isolated in china and characterization of novel hantaviruses isolated from Niviventer confucianus and Rattus rattus.

The antigenic and genetic properties of 46 hantaviruses from China, 13 from patients, 23 from rodents, and 10 from unknown hosts, were compared with those of other hantaviruses. The viruses were classified as either Hantaan (HTN) or Seoul (SEO) viruses. A phylogenetic analysis of the partial M (300 bp) and S (around 485 bp) genomes of HTN viruses identified nine distinct genetic subtypes, one consisting of isolates from Korea. The SEO viruses were divided into five genetic subtypes, although they had less variability than the HTN subtypes. There was a correlation between the subtype and province of origin for four subtypes of HTN viruses, confirming geographical clustering. Hantaan virus NC167 isolated from Niviventer confucianus and SEO virus Gou3 isolated from Rattus rattus were the basal clades in each virus. The phylogenetic trees constructed from the entire S and M segments suggested that NC167 was introduced to N. confucianus in a host-switching event. The reactivity of a panel of 35 monoclonal antibodies was almost exactly the same in NC167 and a representative HTN virus and in Gou3 and a representative SEO virus. However, there was a one-way cross-neutralization between them. These results confirm the varied nature of Murinae-associated hantaviruses in China.

Animals↗

PubMed1988

Nucleotide sequence of the L gene of vesicular stomatitis virus (New Jersey): identification of conserved domains in the New Jersey and Indiana L proteins.

The nucleotide sequence of the L gene of vesicular stomatitis virus, New Jersey serotype (Hazelhurst subtype), was determined. Primer extension dideoxy sequencing of genomic RNA using reverse transcriptase initiated within the adjacent G gene provided a consensus sequence of 6522 nucleotides. The G/L intergenic junction spanned 21 nucleotides and contained a pseudo transcription start signal as well as two sequences (10 and 6 nucleotides in length) which are reiterated within the L coding region. The predicted L mRNA was 6398 nucleotides long and contained a single open reading frame corresponding to an L protein encompassing 2109 amino acids with a MW of 241,546. Comparison of the amino acid sequence of this New Jersey serotype L protein to that previously reported for the L protein of the serologically and genetically distinct Indiana serotype (M. Schubert, G. G. Harmison, and E. Meier (1984). J. Virol. 51, 505-514.) revealed a high degree of functional homology. In addition, six regions (43 to 103 amino acids in length) which displayed a high percentage of identical amino acids (85 to 96%) were identified. Five of these regions were clustered within the amino-terminal half of the L protein. Two of these regions contained sequences, 41 amino acids in length, which were significantly similar to corresponding regions of the L proteins of the paramyxoviruses Sendai and Newcastle disease virus. These structurally conserved regions may correspond to functional domains of the multifunctional L protein.

Amino Acid Sequence↗

PubMed2006

Variable intensity of purifying selection on cytotoxic T-lymphocyte epitopes in hepatitis C virus.

In an analysis of the patterns of nucleotide diversity in 26 datasets providing population-level data on different genomic regions of different hepatitis C virus (HCV) subtypes, known cytotoxic T-lymphocyte (CTL) epitope regions in most cases showed evidence of the occurrence of purifying selection. Two main factors were found to be associated with the strength of purifying selection: (1) purifying selection was stronger in CTL epitopes in non-envelope proteins than in envelope proteins and (2) purifying selection was stronger when the epitope was "matched", i.e., when the described or "canonical" epitope sequence was present unaltered in at least one sequence in the dataset. Of all polymorphic sites, non-synonymous sites in matched CTL epitopes in non-envelope proteins had the lowest gene diversities, implying that these variants are subject to ongoing purifying selection. This in turn suggests that the population frequency of such variants may of be the result of a balance between opposing forces: on the one hand, positive selection favoring escape mutants in hosts that express the presenting MHC molecule and, on the other hand, purifying selection acting, in the absence of the presenting MHC molecule, to reduce the frequency of slightly deleterious variants.

Epitopes, T-Lymphocyte↗

PubMed2002

Toward molecular diagnostics of mood disorders in psychiatry.

Mental disorders are highly prevalent and often difficult to diagnose. There is a significant gap between advances in their pharmacotherapy and the present lack of objective biologic tests for diagnosis. The special complexity of diagnosis in psychiatry is related to the absence of objective diagnostic "gold standards", co-morbidity, heterogeneity and equifinality, quantitative trait loci, and locus heterogeneity. Here, we review recent findings relating to diagnostic, pathophysiological, and linkage markers for mood disorders at the biochemical level involving monoamine neurotransmitters, hormones, and signal-transducing G proteins. Identification of biological diagnostic markers could enable segregating mood disorders to several biologically different subtypes. New-era methods and strategies involving genomics, proteomics, multi-marker approach and single nucleotide polymorphisms have the potential to revolutionize future diagnosis in psychiatry.

Biogenic Monoamines↗

PubMed2006

Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders.

We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein-Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field.

Adaptor Proteins, Signal Transducing↗

PubMed1992

Cloning and functional expression of the canine anaphylatoxin C5a receptor. Evidence for high interspecies variability.

A cDNA clone, DTJP03, encoding an orphan receptor, was isolated from a canine thyroid library, and found to exhibit 68.6% amino-acid identity with the recently described human C5a receptor. This relatively low similarity first suggested that DTJP03 encoded either a C5a receptor subtype, or the presumably related C3a receptor. Binding studies performed on membranes from COS-7 cells expressing the recombinant receptor demonstrated that DTJP03 encoded a high-affinity C5a receptor, with a Kd of 1.2 nM. C3a was unable to compete for C5a binding. Intracellular free calcium concentrations were measured by Quin-2 fluorescence assays in Chinese hamster ovary cells stably transfected with the canine C5a receptor. C5a addition elicited an increase in the intracellular calcium concentration. Extracellular EGTA partially prevented this response, suggesting that activation of the C5a receptor promotes both the release of calcium from intracellular stores, and the influx of extracellular calcium. Genes encoding C5a-receptor subtypes were subsequently searched for by PCR in genomic DNA from human, canine, rat and bovine sources. The result was the amplification of a single gene fragment from each species, with about 70% identity between any two of them. The canine C5a receptor has therefore to be considered as orthologous to the human C5a receptor described previously. The low similarity between C5a receptors from different mammalian species is quite unusual for a G-protein-coupled receptor.

Amino Acid Sequence↗

PubMed2000

Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.

We report a French pedigree with members having an inherited combination of non-epidermolytic palmoplantar keratoderma (NEPPK) and sensorineural deafness. The penetrance of both features was incomplete. Additional ectodermal defects were absent. The expression of numerous epidermal proteins (keratins, fillagrin, cornified envelope proteins, intercellular junction proteins including connexin 26, and loricrin) defined with immunolabelling was normal in the proband. The combination was shown to be associated with the A7445G point mutation in the mitochondrial genome (mtDNA). This mutation is responsible for a subtype of NEPPK which is so far the only mtDNA mutation-associated keratoderma.

Adolescent↗

PubMed2002

Hepatitis C virus: clades and properties.

Hepatitis C virus (HCV) is a member of the virus family Flaviviridae. At present HCV is classified into a discrete hepacivirus genus and is represented by six clades according to genome sequencing. Each clade is further divisible into subtypes, which may prove important for the study of clinical differences and epidemiological studies. Limited homology also exists with hepatitis G/GB viruses, despite the fact that the hepatotropic nature of the latter agents remains contentious. The variability amongst the six HCV clades is less than that observed between the four serotypes of dengue, suggesting that each clade may represent a distinct virus were tests such as plaque neutralization to become available for delineating HCV isolates. The distribution worldwide varies, with Clades 1 and 2 predominating in most regions-an important consideration for the development of any vaccine. In addition, the clade distribution among cohorts may vary according to age. Point source outbreaks of HCV, for example in large numbers of women inadvertently infected with HCV-contaminated anti-D globulin, offers an opportunity to study the evolution of HCV genotypes over several decades. Parallel studies in chimpanzees have shown that the hypervariable region of E2 may play a role in HCV immunity, with quasispecies rapidly replacing the predominant subtype as immunity develops to the initiating virus strain. There is some evidence that an IFN-sensitive motif exists in the NS5 gene which may have some predictive value in determining the likely outcome of IFN treatment. A database is available for all HCV sequences, together with information about their properties and guidance for the evaluation of new isolates (http://s2as02.genes.nig.ac.jp).

Age Factors↗

PubMed2001

Predicted amino acid sequences for 100 JCV strains.

DNA sequence variation between JCV genotypes is confined largely to noncoding intergenic regions and introns. Nevertheless, evidence suggests that the amino acid sequence variations among the 8 genotypes of JCV can influence the potential for neurovirulence of the virus. In the current study, the amino acid sequences for 100 JCV genomes were translated and grouped into genotype families. Subtype consensus sequences were determined and the type-specific amino acid sequence variants were identified.

Amino Acid Sequence↗

PubMed2004

Molecular genotyping of methicillin-resistant Staphylococcus aureus strains in a teaching hospital in Turkey.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of nosocomial infections in our hospital. Therefore, we aimed to characterize MRSA isolates phenotypically from patients with nosocomial infections at Cumhuriyet University Hospital between December, 1999, and June, 2001, in Sivas by analysis of antibiotic patterns and genotypically using pulsed-field gel electrophoresis (PFGE) and repetitive element sequence-based polymerase chain reaction (rep-PCR). Forty-three nosocomial isolates were collected from various wards. All isolates were resistant to penicillin, tetracycline, oxacillin, and gentamicin. By rep-PCR and by separation of SmaI fragments of genomic DNA using PFGE, one major type (eight subtypes with PFGE) was identified among the strains. This clone was found to be different than some clones such as Iberian, Brazilian, and a major clone that was found in another Turkish University Hospital in Ankara. According to our results, there is a major MRSA clone with a potential to spread in our hospital. Infection control measures should be directed toward restricting the further spread of this clone. Therefore, in accordance with these findings, a surveillance culturing program should be established.

Bacterial Typing Techniques↗