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1.
Microbiol Resour Announc ; : e0086723, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38809066

ABSTRACT

We report here the complete genome of one Salmonella Agona strain isolated in 2017 from a dried milk powder in France.

2.
Nat Commun ; 12(1): 6097, 2021 10 20.
Article in English | MEDLINE | ID: mdl-34671037

ABSTRACT

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antiviral Agents/administration & dosage , COVID-19 Drug Treatment , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Lung/metabolism , Lung/virology , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , SARS-CoV-2/isolation & purification , Tissue Distribution , Viral Load
3.
Cell ; 184(5): 1188-1200.e19, 2021 03 04.
Article in English | MEDLINE | ID: mdl-33577765

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Macaca fascicularis , Spike Glycoprotein, Coronavirus/chemistry , Animals , Antibodies, Neutralizing , B-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Mice , Mice, Inbred BALB C , Models, Animal , Nanoparticles/administration & dosage , Rabbits , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/blood , T-Lymphocytes/immunology , Viral Load
4.
J Low Genit Tract Dis ; 24(1): 53-60, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31860576

ABSTRACT

OBJECTIVES: A subset of vulvar carcinomas (VC) are associated with human papillomavirus (HPV) DNA. This trait can be used to identify tumor markers for patient's follow-up. A large diversity of HPV prevalence in VC has been reported, but no data are available concerning the insertional HPV status in this tumor type. Therefore, we have used an innovative next generation sequencing (NGS)-based CaptHPV method able to provide an extensive characterization of HPV DNA in tumors. MATERIAL AND METHODS: Tumor tissue specimens from 55 patients with VC were analyzed using p16 immunohistochemistry, in situ hybridization, polymerase chain reaction, and CaptHPV-NGS assays. RESULTS: Our analyses showed that 8 (14.5%) of 55 cases were associated with HPV 16 DNA. No other HPV genotypes were identified. The HPV genome was in a free episomal state only in one case and both episomal and integrated into the tumor cell genome in 7. There was a single insertion in 5 cases and multiple sites, scattered at different chromosomal loci in two. ISH data suggest that some of these might reflect tumor heterogeneity. Viral integration targeted cellular genes among which were TP63, CCDC148, LOC100133091, PKP1, and POLA2. Viral integration at the PKP1 locus was associated with partial gene deletion, and no PKP1 protein was detected in tumor tissue. CONCLUSIONS: Using the NGS-based innovative capture-HPV approach, we established a cartography of HPV 16 DNA in 8 VC cases and identified novel genes targeted by integration that may be used as specific tumor markers. In addition, we established a rationale strategy for optimal characterization of HPV status in VC.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma/diagnosis , DNA, Viral/genetics , High-Throughput Nucleotide Sequencing , Human papillomavirus 16/genetics , Virus Integration , Vulvar Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Carcinoma/pathology , Carcinoma/virology , DNA, Viral/chemistry , Female , Genetic Markers , Humans , Middle Aged , Vulvar Neoplasms/pathology , Vulvar Neoplasms/virology
5.
Sci Rep ; 8(1): 4321, 2018 03 12.
Article in English | MEDLINE | ID: mdl-29531245

ABSTRACT

Human cytomegalovirus (HCMV) primary infections of pregnant women can lead to congenital infections of the fetus that could have severe impacts on the health of the newborn. Recent studies have shown that 10-100 billion DNA fragments per milliliter of plasma are circulating cell-free. The study of this DNA has rapidly expanding applications to non-invasive prenatal testing (NIPT). In this study, we have shown that we can detect viral specific reads in the massively parallel shotgun sequencing (MPSS) NIPT data. We have also observed a strong correlation between the viral load of calibration samples and the number of reads aligned on the reference genome. Based on these observations we have constructed a statistical model able to quantify the viral load of patient samples. We propose to use this new method to detect and quantify circulating DNA virus like HCMV during pregnancy using the same sequencing results as NIPT data. This method could be used to improve the NIPT diagnosis.


Subject(s)
Cytomegalovirus Infections/diagnosis , Cytomegalovirus/genetics , DNA, Viral/genetics , High-Throughput Nucleotide Sequencing/methods , Pregnancy Complications, Infectious/diagnosis , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/isolation & purification , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/blood , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/virology , DNA, Viral/blood , DNA, Viral/isolation & purification , Female , Genomics , Humans , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/genetics , Pregnancy Complications, Infectious/virology , Prenatal Diagnosis/methods , Proof of Concept Study , Viral Load
6.
Blood ; 129(4): 484-496, 2017 01 26.
Article in English | MEDLINE | ID: mdl-27856460

ABSTRACT

Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38- hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34+ progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies.


Subject(s)
Chromosomes, Human, Pair 5 , Hematopoietic Stem Cells/metabolism , Leukemia, Myeloid, Acute/genetics , Lymphocytes/metabolism , Mutation , Myelodysplastic Syndromes/genetics , Myeloid Cells/metabolism , ADP-ribosyl Cyclase 1/deficiency , ADP-ribosyl Cyclase 1/genetics , Animals , Antigens, CD34/genetics , Antigens, CD34/metabolism , Antigens, Nuclear/genetics , Antigens, Nuclear/metabolism , Cell Cycle Proteins , Cell Differentiation , Cell Lineage/genetics , Clone Cells , Disease Progression , Female , Gene Expression , Gene Knockdown Techniques , Hematopoietic Stem Cells/pathology , Humans , Immunophenotyping , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Lymphocytes/pathology , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred NOD , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Myeloid Cells/pathology , Phenotype , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transplantation, Heterologous
7.
Blood ; 127(6): 749-60, 2016 Feb 11.
Article in English | MEDLINE | ID: mdl-26626993

ABSTRACT

Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin ß. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clonal Evolution/drug effects , Myelodysplastic Syndromes/drug therapy , Thalidomide/analogs & derivatives , Aged , Anemia, Macrocytic/drug therapy , Anemia, Macrocytic/genetics , Anemia, Macrocytic/pathology , Cell Proliferation/drug effects , Cell Proliferation/genetics , Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Clonal Evolution/genetics , Clone Cells/drug effects , Clone Cells/metabolism , Clone Cells/pathology , DNA Mutational Analysis , Erythropoietin/administration & dosage , Female , Humans , Lenalidomide , Male , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Recombinant Proteins/administration & dosage , Thalidomide/administration & dosage , Thalidomide/pharmacology , Treatment Outcome
8.
Blood ; 122(18): 3169-77, 2013 Oct 31.
Article in English | MEDLINE | ID: mdl-24047651

ABSTRACT

Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.


Subject(s)
Mutation , Myelodysplastic Syndromes/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Acute Disease , Adult , Aged , Aged, 80 and over , Cohort Studies , Core Binding Factor Alpha 2 Subunit/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , DNA Mutational Analysis , Exome/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Frequency , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Male , Middle Aged , Multivariate Analysis , Reverse Transcriptase Polymerase Chain Reaction
10.
Blood ; 119(14): 3211-8, 2012 Apr 05.
Article in English | MEDLINE | ID: mdl-22343920

ABSTRACT

A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.


Subject(s)
Mutation , Myelodysplastic Syndromes/genetics , Phenotype , RNA Splicing/genetics , Adult , Aged , Aged, 80 and over , Cell Transformation, Neoplastic/genetics , Female , Genetic Association Studies , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/mortality , Nuclear Proteins/genetics , Phosphoproteins/genetics , Prognosis , RNA Splicing Factors , Ribonucleoprotein, U2 Small Nuclear/genetics , Ribonucleoproteins/genetics , Serine-Arginine Splicing Factors , Splicing Factor U2AF , Survival Analysis
11.
Oncotarget ; 3(11): 1284-93, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23327988

ABSTRACT

The recently discovered spliceosome mutations represent a group of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDS), chronic myelomonocytoic leukemia (CMML) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype correlations have been observed, including the clustering of ring sideroblasts with SF3B1 mutations in MDS. Spliceosome mutations might result in defective small nuclear ribonucleoprotein complexes assembly on the pre-mRNA, deregulated global and alternative mRNA splicing, nuclear-cytoplasm export, and unpliced mRNA degradation, and thus may alter the expression of multiple genes. In the current review, we discuss the potential role of these mutations in cell transformation and how they could impact the therapeutic approaches.


Subject(s)
Leukemia, Myelomonocytic, Chronic/genetics , Mutation , Myelodysplastic Syndromes/genetics , RNA Splicing/genetics , Spliceosomes/genetics , Animals , Humans
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