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PubMed1994

Sequence variability of hepatitis C virus and its clinical relevance.

Chronic type C hepatitis is a potentially serious disease that can lead to cirrhosis and hepatocellular carcinoma. This complex disease is caused by the hepatitis C virus (HCV), a positive sense, single-stranded RNA virus. HCV has been assigned to a separate genus within the Flaviviridae, and shares a close relationship to the pestiviruses. Nucleotide sequence variation has been observed in genomes amplified from serum of patients with HCV infection, and cloning of RNA amplified from patients infected with HCV has confirmed the heterogeneity of the agent responsible for post-transfusion and sporadic hepatitis C. The variability of HCV is structured in a way that immediately suggests a two tiered classification: this nomenclature comprises 'types' corresponding to the major branches in a phylogenetic tree of sequences from genomic or subgenomic regions of the genome, and 'subtypes', corresponding to the more closely related sequences within some of the major groups. This genotyping designation has provided an epidemiological tool for studying geographical differences in hepatitis C infection. Clearly discernible patterns of genotype distribution have been found in those countries that have been studied so far. In many European countries genotype distributions vary with the age of patients, reflecting rapid changes in genotype distribution with time within a single geographical area. Unfortunately we know very little about modes of transmission within different communities. There is considerable interest in the clinical significance of different HCV genotypes, and the intriguing question of whether these differences may affect the spectrum of the disease associated with hepatitis C. These data also have implications for diagnosis and treatment of acute and chronic hepatitis C. A uniform typing scheme and nomenclature will facilitate our understanding of the disease caused by this virus worldwide.

Genotype↗
PubMed1994

Genomic analysis of the F subtypes of human complement factor B.

Factor B of human complement is encoded within the Major Histocompatibility Complex (MHC) and is polymorphic, with up to 30 alleles defined by electrophoretic mobility. One of the most common alleles, BF*F, is subdivided into the FA and FB subtypes, which differ at the gene level by non-synonymous base substitutions in the seventh codon. We have found at this position a new restriction site polymorphism, as a Bsl I site absent from the FB allele. Using this restriction polymorphism, we have developed a method for BF F subtype determination, based on amplification by polymerase chain reaction of the 5' end of the BF gene, and digestion with Bsl I. This new method has been applied to a panel of 29 selected BF F individuals. A single strand DNA conformation analysis of the same region of the gene allowed us to confirm the above DNA-based BF F subtyping. During this study, two BF*F1 alleles showed discrepancies between protein and DNA typing, which were confirmed by our sequencing data. These were identical, in the 5' region, to BF*S and BF*FB genes, respectively. In a comparison with two protein subtyping methods, identical results were found for only one third of the selected samples. The conflicting results may arise, in part, from previously undescribed molecular heterogeneity within BF F subtypes, or from the presence of a null allele. Our new method allows BF*F subtyping to be used with confidence in the definition of disease-associated MHC haplotypes.

Alleles↗
PubMed2004

Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load.

An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

Amino Acid Sequence↗
PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗
PubMed2005

Accumulation of an intron-retained mRNA for granulocyte macrophage-colony stimulating factor receptor common beta chain in neutrophils of myelodysplastic syndromes.

We recently identified a reduction in the neutrophil surface expression of common beta chain (beta c) of the receptor for granulocyte macrophage-colony stimulating factor (GM-CSF) in the patients with myelodysplastic syndromes (MDS). To determine the etiology of the impaired beta c expression, beta c mRNA from neutrophilic granulocytes of MDS patients and healthy controls was analyzed by a combination of direct reverse transcriptase-polymerase chain reaction-based single-strand conformational polymorphism and sequencing. Nine different beta c transcripts were detected, but none was specific for MDS. However, one of the transcripts (beta c79) containing a 79-base intron insertion between exons V and VI was significantly increased in MDS. This 27-kd isoform consisted of the beta c N-terminal 182 amino acids followed by a new 84-amino-acid sequence. beta c79 was overexpressed in all MDS subtypes. No genomic mutations were detected within the intron or at the intron/exon boundaries. The isoform is predominantly located in the cytoplasm by Western blot analysis and was unable to generate high-affinity binding sites or transduce a signal for proliferation when coexpressed with the receptor for human GM-CSF alpha chain. Our study suggests that the accumulation of the abnormal beta c transcripts with intron V retention results in the reduction in cell-surface expression of beta c observed in MDS.

Adult↗
PubMed2006

Isolation and pulsed-field gel electrophoresis typing of Listeria monocytogenes from modified atmosphere packaged fresh-cut vegetables collected in Ireland.

The incidence of Listeria monocytogenes in modified atmosphere packaged fresh-cut fruits and vegetables from chill cabinets of a supermarket in Ireland was investigated over a 2-year period. Overall, 9.58% of fresh-cut produce was contaminated with Listeria spp. Various species of Listeria were isolated from samples, including L. monocytogenes, L. seeligeri, L. innocua, L. welshimeri, and L. ivanovii. No fruit samples contained detectable L. monocytogenes. Overall, a total of 21 L. monocytogenes isolates (2.9% of samples) were recovered from a range of products, including dry coleslaw mix (80% shredded cabbage and 20% shredded carrot), bean sprouts, and leafy vegetables such iceberg, romaine, and radicchio lettuce and mixed salad leaves (curly endive, escarole, and radicchio leaves). Dry coleslaw mix appeared to have the highest incidence of Listeria contamination (20%) compared with other products. Listeria contamination was more frequent (P < 0.05) during the summer and autumn months than during the winter and spring months. The 21 L. monocytogenes isolates were subsequently subtyped by genomic macrorestriction techniques using ApaI with pulsed-field gel electrophoresis (PFGE). PFGE of digested DNA produced bands of 79 to 518 kb. Four PFGE profiles were identified, and approximately 50% of the isolates were associated with profile 1. This study indicates that fresh-cut vegetables packaged under a modified atmosphere can support growth of numerous species of Listeria, including L. monocytogenes.

Carbon Dioxide↗
PubMed2002

Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors.

The genetic nature of testicular germ cell tumors and the molecular mechanisms underlying the morphological and clinical differences between the two subtypes, seminomas and nonseminomas, remains unclear. Genetic studies show that both subtypes exhibit many of the same regional genomic disruptions, although the frequencies vary and few clear differences are found. We demonstrate significant epigenetic differences between seminomas and nonseminomas by restriction landmark genomic scanning. Seminomas show almost no CpG island methylation, in contrast to nonseminomas that show CpG island methylation at a level similar to other solid tumors. We find an average of 1.11% of CpG islands methylation in nonseminomas, but only 0.08% methylated in seminomas. Furthermore, we demonstrate that seminomas are more highly hypomethylated than nonseminomas throughout their genome. Since both subtypes are thought to arise from primordial germ cells, the epigenetic differences seen between these subtypes may reflect the normal developmental switch in primordial germ cells from an undermethylated genome to a normally methylated genome. We discuss these findings in relation to different developmental models for seminomatous and nonseminomatous testicular germ cell tumors.

Blotting, Southern↗
PubMed2026

Whole genome sequencing of unusual Hepatitis C virus subtypes and drug resistance analysis during direct-acting antiviral therapy in India.

INTRODUCTION AND OBJECTIVES: Pangenotypic direct-acting antivirals (DAA) are effective against highly prevalent Hepatitis C virus (HCV) subtypes, but have been clinically validated almost exclusively in high-income countries. Unusual HCV subtypes may carry natural polymorphisms, potentially impacting DAA susceptibility. We conducted full-genome characterization and resistance analysis of unusual HCV subtypes in patients receiving DAA treatment. PATIENTS AND METHODS: In this prospective hospital-based study, eligible patients were screened for anti-HCV antibodies and active infection was confirmed by diagnostic 5'NCR-based HCV RNA detection. Genotyping was performed by core region sequencing, and viral load quantified by real-time PCR. For whole genome sequencing, multiplex primers were designed using alignments of global reference sequences. Sequencing was carried out using the Oxford Nanopore Technology platform. Phylogenetic analysis used multiple sequence alignment and the HCV-GLUE resource for resistance-associated substitution (RAS) analysis. RESULTS: Predominant genotype was genotype 3 in 64.3% (n = 45); genotype 6 in 21.4% (n = 15); and genotype 1 in 14.2% (n = 10). Unusual HCV subtype 6xa was detected in two patients and showed no NS5A resistance mutations. One genotype 3b patient relapsed at 24 weeks post-DAA treatment completion and carried NS5A resistance-associated substitutions 30 K and 31 M both at baseline and at relapse, conferring high-level resistance to NS5A inhibitors. CONCLUSION: This is the first report from India of whole genome sequencing of HCV subtype 6xa. The identification of NS5A resistance mutations in the 3b relapse case underscores challenges for global HCV elimination strategies.

Humans↗
PubMed2006

Full-length genome analysis of human immunodeficiency virus type 1 subtype C in Brazil.

The most prevalent HIV-1 clade in the global epidemics is C, and this clade is also becoming important in the Brazilian epidemics. In this study, we characterized HIV-1 subtype C variants by sequencing their near full-length genomes. DNA was extracted from six samples previously classified in our laboratory as subtype C on the basis of partial genome sequencing. Amplification was carried out by overlapping PCR followed by direct sequencing. Phylogenetic analysis of full length genomes confirmed that all isolates belonged to subtype C, which formed a highly supported monophyletic cluster and showed a nucleotide distance of 5.4%. The core promoter of all isolates contained three NF-kappaB binding motifs. Our results suggest that subtype C viruses circulating in Brazil were likely introduced recently from a unique point source. The independent clustering of Brazilian subtype C on the phylogenetic tree suggests the profile of an ideal local candidate for the development of a single subtype vaccine.

Brazil↗
PubMed1999

Characterization of subtype A HIV-1 from Africa by full genome sequencing.

OBJECTIVE: To improve our understanding of the genetic complexity of HIV-1 subtype A by increasing the number of subtype A isolates that have been sequenced in their entirety. METHODS: Nine HIV-1-seropositive patients from Africa living in Sweden contributed peripheral blood mononuclear cells (PBMC) for this study. Sequencing of the C2-V3 region of env had shown them to be subtype A. DNA from virus cultures was used for the amplification of virtually full-length proviral sequences, and the resulting fragment was sequenced. RESULTS: Six of the nine viral isolates were subtype A throughout the genome, or non-recombinant, and all of these were from east Africa. One virus from the Ivory Coast had the AG(IbNG) genetic form, a recombinant form common in west Africa. Two of the isolates were novel recombinants: one was an A/C recombinant and the other was A/D. Analysis of gag reveals three subclusters within the A subtype: one containing the AG(IbNG) subtype viruses, one containing the AE(CM240) viruses and one containing the non-recombinant A viruses. These genetic clusters have different geographical distributions in Africa. CONCLUSION: The prevailing view of HIV-1 subtype A forming a uniform band across the center of sub-Saharan Africa needs revision. In all probability, the most common subtype in west Africa and west central Africa is the AG recombinant, AG(IbNG), whereas in east central Africa it is the non-recombinant subtype A.

Africa↗
PubMed2006

[Genomic profile in high risk neuroblastoma by comparative genomic hybridization].

Different subtypes of neuroblastoma (NB) carry associated genetic aberrations that predict their clinical course. Whole chromosome gains are usually associated with early clinical stages and good prognosis, while 1p deletion, 17q gain and MYCN amplification (MNA) are related to advanced stages and poor prognosis. High-risk neuroblastomas (NB-HR) include NB in children aged more than 1 year old, either stage 4 or any stages showing MNA except stage 1. The prognosis of NB-HR patients remains poor, despite aggressive therapy. Only MNA confers poor prognosis. Between January 2000 and February 2005, tumoral specimens from 60 patients with NB-HR were sent to the Spanish Reference Center for NB biological studies. In all cases, MYCN together with 1p36 status was analyzed by fluorescence in situ hybridization (FISH). Comparative genomic hybridization (CGH) was performed in 24 cases. Using FISH we detected 31 MNA cases including 29 with 1p36 deletion; there were 21 cases without MYCN amplification (MNNA) but 7 of these had 1p36 deletion; 8 cases showed MYCN gain (MNG) but 6 of these had 1p36 deletion. CGH showed other chromosomal alterations. Of 11 MNA cases, none had 11q loss and all of them showed 17q gain or 17 disomy. Of the 7 MNNA cases, there were 4 with 11q loss including 2 with 3p loss and all presented 17q gain or 17 disomy. The 6 MNG cases included 4 cases with 11q loss and 5 cases with 17q gain or 17 disomy. Genomic profiling by CGH in NB-HR confirms the interaction among genetic alterations, the prognostic significance of which should be evaluated to establish new treatment criteria.

Female↗
PubMed1989

Cloning of ligand-specific cell lines via gene transfer: identification of a D2 dopamine receptor subtype.

Using rat genomic DNA, we have established a transfected mouse fibroblast cell line that expresses a spiperone binding site with the pharmacological characteristics of a D2 dopamine receptor. The expressed D2 receptors are the product of a gene that is distinct from that reported by Bunzow et al. [Bunzow, J. R., Van Tol, H. H. M., Granoly, D. K., Albert, P., Salon, J., Christie, M., Machida, C. A., Neve, K. A. & Civelli, O. (1988) Nature (London) 336, 783-787]. Flow cytometry with the Ca2+-sensitive dye indo-1 demonstrated that activation of the expressed D2 sites resulted in increases in intracellular calcium that were dependent on the influx of external Ca2+. These general cloning procedures should be applicable to the production of cell lines expressing a variety of genes for which only functional assays are available.

Animals↗
PubMed2003

Genetic subtyping of renal cell carcinoma by comparative genomic hybridization.

The prognosis of renal cell carcinoma (RCC) varies dependent on histologic tumor subtypes. However, differentiation between RCC types may sometimes be difficult on histologic grounds alone. Furthermore, the prognostic value of histologic parameters for the individual prognosis is limited. Additional information on the molecular level seems necessary to obtain more certainty in diagnostic and prognostic evaluation. By investigating genetic alterations in different RCC subtypes, we sought to obtain a genotype-phenotype correlation. Eighty-two clear-cell, 53 papillary, 23 chromophobe RCCs and 26 renal oncocytomas were investigated. Comparative genomic hybridization (CGH) was performed on DNA from paraffin-embedded tissue samples. DNA was isolated from tumor areas by microdissection and amplified by degenerated oligonucleotide primed polymerase chain reaction (DOP-PCR). CGH was performed according to standard protocols. We were able to detect specific alterations in each RCC subtype: clear cell RCC showed -3p, +5/5q, -8p, -9, -14, -18; papillary (chromophilic) RCC gains of chromosomes 7, 17, 16, 3, 12; chromophobe RCC loss of chromosomes 1, 2, 6, 10, 13, 17, 21; renal oncocytomas loss of chromosomes 1/1p and 14. Furthermore, for clear cell RCC, it was possible to define alterations which are associated with metastatic disease: loss of 9, 10, 14. Our results demonstrate that each RCC subtype is characterized by distinct genetic alterations. The definition of genetic alterations seems helpful for a tumor typing especially when morphology is equivocal. Therefore, genetic analyses represent a powerful diagnostic and prognostic tool for RCC.

Carcinoma, Renal Cell↗
PubMed1992

Association of Epstein-Barr virus genome with mixed cellularity and cellular phase nodular sclerosis Hodgkin's disease subtypes.

Association of Epstein-Barr virus (EBV) genome with Hodgkin's disease (HD) histological subtypes was investigated using the polymerase chain reaction (PCR). A highly significant association of EBV genome with the mixed cellularity (MC) subtype (10 positive out of 15 cases; 66%) was observed, suggesting a possible etiopathogenetic role of EBV in the induction of this subset. By contrast, a markedly lower frequency of association with EBV genome was found in nodular sclerosis (NS) (12 positive out of 46 cases; 26%) and in nodular lymphocytic predominance (NLP) (0 positive out of 5 cases) HD subtypes. In addition, in the NS series, the presence of EBV genome was mainly restricted to the 'cellular phase' NS subset. This finding strengthens the possibility, suggested by clinico-pathological features and survival rates, that 'cellular phase NS' is a disease more akin to MC than to typical NS HD.

Genome, Viral↗
PubMed1993

Identification of a new hepatitis B virus (HBV) genotype from Brazil that expresses HBV surface antigen subtype adw4.

The complete genome of a hepatitis B virus (HBV) from Brazil that expressed the subtype adw4 of HBV surface antigen (HBsAg) was cloned and sequenced. The genome, termed w4B, consists of 3215 bp. The overall genetic organization of typical hepadnaviruses with four open reading frames including the preC region was found to be conserved. When comparing the w4B sequence with 19 complete HBV genomes it was, however, found to be more divergent (15%) than any other HBV sequence thus far reported. Until now, no more than 11% divergence has been reported. Distinct from the five known HBV genotypes A to E, w4B made up a new, sixth genotype. The importance of the conserved third start codon in the HBV X gene became apparent in isolate w4B. By mutation, this ATG was out of frame, and by what appears to have been a linked mutation, a new start site two codons downstream was re-established. The significance of several other mutations is discussed.

Amino Acid Sequence↗
PubMed2005

A monoclonal antibody-based ELISA allows discrimination between responses induced by bovine herpesvirus subtypes 1 (BoHV-1.1) and 2 (BoHV-1.2).

Bovine herpesvirus type 1 (BoHV-1) has distinct subtypes according to genomic characterization. Immune responses induced by BoHV-1 subtype 1 (BoHV-1.1) are not distinguishable from those induced by BoHV-1 subtype 2 (BoHV-1.2) through conventional serological methods. In the present report, an enzyme linked immunosorbent assay is described that allows discrimination between immune responses in cattle immunized with either subtype, based on a monoclonal antibody that recognizes specifically the amino-terminal region of glycoprotein C (gC) on BoHV-1.1 strains, thus not reacting with BoHV-1.2a. The test displayed a sensitivity of 92%, specificity of 90% and a good correlation with serum neutralization tests on samples from BoHV-1.1-immunized calves (kappa = 0.799). The test may be useful to provide new insights into the roles played by each of these two subtypes in the epidemiology of BoHV-1 infections.

Animals↗
PubMed2005

Analysis of full-length human immunodeficiency virus type 1 genome reveals a variable spectrum of subtypes B and f recombinants in São Paulo, Brazil.

Recombination is one of the major mechanisms contributing to human immunodeficiency virus type 1 (HIV-1) variability. Analysis of pol gene sequences of 215 HIV-1 samples from São Paulo, Brazil classified 189 sequences as subtype B (87.9%), 8 sequences as subtype F (3.7%), and 18 sequences (8.4%) as B/F recombinants. After the analysis of the pol gene, a subset of six recombinant samples composed of sequences with a related recombinant pol structure was selected for full-length genome analysis to identify a possible circulating recombinant form. According to full-length genome analysis, recombination was higher in gag, protease, reverse transcriptase, integrase, and vif. Identification of many distinct recombinant forms and the absence of an identifiable HIV-1 circulating recombinant form suggest that a high frequency of dual infections between HIV-1 subtypes B and F is occurring in São Paulo, Brazil.

Brazil↗