Paris Descartes University

About: Paris Descartes University is a government organization based out in Paris, France. It is known for research contribution in the topics: Population & Immune system. The organization has 20987 authors who have published 37456 publications receiving 1206222 citations. The organization is also known as: Université Paris V-Descartes & Université de Paris V.

Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia

Abstract: Blood disorders caused by abnormal β-globin — β-thalassaemia and sickle cell disease — are the most prevalent inherited disorders worldwide, with patients often remaining dependent on blood transfusions throughout their lives So a report of the successful use of gene therapy in a case of severe β-thalassaemia — using a lentiviral vector expressing the β-globin gene — is an eagerly awaited event More than two years after gene transfer, the adult male patient has been transfusion-independent for 21 months The therapeutic benefit seems to result from a dominant, myeloid-biased cell clone that may remain benign, although it could yet develop into leukaemia — a reminder that gene therapy is still at an early stage Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia The β-haemoglobinopathies are the most prevalent inherited disorders worldwide Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2 The βE-globin allele bears a point mutation that causes alternative splicing The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2 When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2 The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells

Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic–Uremic Syndrome

Abstract: A b s t r ac t Background Atypical hemolytic–uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemo lytic–uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infu sion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event–free status (no de crease in the platelet count of >25%, no plasma exchange or infusion, and no initia tion of dialysis) (in trial 2). Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10 9 per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event–free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculiz umab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in healthrelated quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the exten

STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration

Abstract: Diagnostic accuracy studies are, like other clinical studies, at risk of bias due to shortcomings in design and conduct, and the results of a diagnostic accuracy study may not apply to other patient groups and settings. Readers of study reports need to be informed about study design and conduct, in sufficient detail to judge the trustworthiness and applicability of the study findings. The STARD statement (Standards for Reporting of Diagnostic Accuracy Studies) was developed to improve the completeness and transparency of reports of diagnostic accuracy studies. STARD contains a list of essential items that can be used as a checklist, by authors, reviewers and other readers, to ensure that a report of a diagnostic accuracy study contains the necessary information. STARD was recently updated. All updated STARD materials, including the checklist, are available at http://www.equator-network.org/reporting-guidelines/stard. Here, we present the STARD 2015 explanation and elaboration document. Through commented examples of appropriate reporting, we clarify the rationale for each of the 30 items on the STARD 2015 checklist, and describe what is expected from authors in developing sufficiently informative study reports.

B cells and tertiary lymphoid structures promote immunotherapy response

Abstract: Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

Abstract: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.