Longitudinal immunomonitoring following Tocilizumab in rheumatoid arthritis

Poster presentationInternational audienc

Response to Treatment and Disease Progression Linked to CD4+ T Cell Surface CC Chemokine Receptor 5 Density in Human Immunodeficiency Virus Type 1 Vertical Infection

The factors governing interindividual variability in disease progression among children vertically infected with human immunodeficiency virus type 1 (HIV-1) remain unclear. Because it has recently been shown in infected adults that the density of CC chemokine receptor 5 (CCR5) molecules at the surface of nonactivated (human leukocyte antigen [HLA]-DR-) CD4+ T cells correlates with disease progression, the same correlation was sought in children. HLA-DR-CD4+ T cell surface CCR5 density was constant over time and correlated with the bioclinical stage and with the CD4 cell slope observed before antiretroviral treatment. In addition, CCR5 density was negatively correlated with the intensity of the decrease in viremia during antiretroviral therapy and was positively correlated with CD4 cell slope since birth. These results are compatible with the hypothesis that CCR5 density is a key factor governing disease progression in pediatric HIV-1 infection and, thereby, an indicator of prognosis. Moreover, they suggest that therapies aimed at reducing CCR5 accessibility should slow down HIV disease evolution in childre

Small-Molecule Inhibition of HIV pre-mRNA Splicing as a Novel Antiretroviral Therapy to Overcome Drug Resistance

The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16) that interferes with exonic splicing enhancer activity of the SR protein splicing factor SF2/ASF suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles. IDC16 inhibits replication of macrophage- and T cell–tropic laboratory strains, clinical isolates, and strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Importantly, drug treatment of primary blood cells did not alter splicing profiles of endogenous genes involved in cell cycle transition and apoptosis. Thus, human splicing factors represent novel and promising drug targets for the development of antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses

Ten Years’ Experience with Alendronate for Osteoporosis in Postmenopausal Women

Background Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. Methods The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. Results Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. Conclusions The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects

CD8+ T Cells from Human Neonates Are Biased toward an Innate Immune Response

To better understand why human neonates show a poor response to intracellular pathogens, we compared gene expression and histone modification profiles of neonatal naive CD8+ T cells with that of their adult counterparts. We found that neonatal lymphocytes have a distinct epigenomic landscape associated with a lower expression of genes involved in T cell receptor (TCR) signaling and cytotoxicity and a higher expression of genes involved in the cell cycle and innate immunity. Functional studies corroborated that neonatal CD8+ T cells are less cytotoxic, transcribe antimicrobial peptides, and produce reactive oxygen species. Altogether, our results show that neonatal CD8+ T cells have a specific genetic program biased toward the innate immune response. These findings will contribute to better diagnosis and management of the neonatal immune response.This project was specifically supported by a joint EcosNord-Anuies-SEP-Con-acyt project (M11S01). Work in the M.A.S. laboratory is supported by grantsfrom Consejo Nacional de Ciencia y Tecnologı ́a(CONACYT; CB-2011-01168182) and Programa de Mejoramiento del Profesorado (PROMEPSI-UAEM/13/342). Work in the S.S. laboratory is supported by recurrent fundingfrom the Inserm and Aix-Marseille University and by specific grants from theEuropean Union’s FP7 Program (agreement 282510-BLUEPRINT), the Associ-ation pour la Recherche contre le Cancer (ARC) (project SFI20111203756), andthe Aix-Marseille initiative d’excelence (A*MIDEX) project ANR-11-IDEX-0001-02. We thank Centro Estatal de la Transfusio ́n Sanguı ́nea in Cuernavaca for thedonation of leukocyte concentrates and the mothers and babies of HospitalGeneral Parres in Cuernavaca for the donation of cord blood. This study makesuse of data generated by the Blueprint and Roadmap consortia. A full list of theinvestigators who contributed to the generation of the data is availablefromwww.blueprint-epigenome.euandhttp://www.roadmapepigenomics.org/. Funding for the Blueprint project was provided by the European Union’sSeventh Framework Program (FP7/2007-2013) under grant agreement282510 – BLUEPRINT. The Roadmap consortium is financed by the NIH. Weare grateful to Professor C.I. Pogson for critical reading of the manuscript.S

Validation of the Body Concealment Scale for Scleroderma (BCSS): Replication in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort

© 2016 Elsevier Ltd Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages

Valeur pronostic de la densité membranaire en CXCR4 dans la LAL-B (Leucémie aïgue lymphoblastique de la lignée B) de l'enfant

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

High Expression of Fas/CD95 on CD4+ Circulating T Cells: An Exclusion Criterion in the Diagnosis of Mycosis Fungoides?

International audienceThe aim of this 10-year monocentric prospective study was to determine a cut-off value of Fas/CD95 expression by peripheral blood CD4+ T lymphocytes in discriminating patients with mycosis fungoides from controls with cutaneous benign lymphocytic conditions. CD95 expression in peripheral blood CD4+ T lymphocytes was measured using flow cytometry in 330 patients referred for diagnosis: 104 with mycosis fungoides and 226 with eczema, psoriasis, drug reaction, etc. The sensitivity and specificity of different thresholds of CD95 expression were calculated regarding the final diagnosis of patients with mycosis fungoides or controls. CD95 expression higher than 30% reached a specificity of 91% in ruling out a diagnosis of mycosis fungoides, although overall CD95 expression was not significantly different from that of controls (p = 0.309) and sensitivity was very low (5%). Thus, peripheral CD95 expression higher than 30% could be used among the exclusion criteria in a multicomponent score for mycosis fungoides diagnosis

Distal Pancreatectomy with Celiac Axis Resection (Modified Appleby Procedure) and Arterial Reconstruction for Locally Advanced Pancreatic Adenocarcinoma After FOLFIRINOX Chemotherapy and Chemoradiation Therapy

International audienceBackground: Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028–1061, 2017. https://doi.org/10.6004/jnccn.2017.0131; Isaji S et al. in Pancreatology 18(1):2–11, 2018. https://doi.org/10.1016/j.pan.2017.11.011). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801–10, 2016. https://doi.org/10.1016/s1470-2045(16)00172-8; Pietrasz D et al. in Ann Surg Oncol 26(1):109–117, 2019. https://doi.org/10.1245/s10434-018-6931-6). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment.Patient: This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection.Technique: The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues, en bloc resection (Strasberg SM et al. in Surgery 133(5):521–527, 2003. https://doi.org/10.1067/msy.2003.146), and primary end-to-end arterial reconstruction.Conclusion: A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of en bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention

Plasma Level of Soluble ST2 in Chronically Infected HIV-1 Patients with Suppressed Viremia

International audienceINTRODUCTION : Interleukin-33 (IL-33) is a cell damage-induced alarmin. The plasma concentration of suppression of tumorogenicity (sST2), a surrogate marker of IL-33 production, is a prognostic marker of cardiovascular disease.OBSERVATION : Recently, we reported that sST2 plasma levels were elevated in early HIV-1 infection and linked to markers of microbial translocation and of T cell activation.RESULTS : Here we show that it is not the case in patients with suppressed viremia. Thus, IL-33 plays its alarmin role only during the early phase of the infection