A contribution to the debate on tinnitus definition.

Tinnitus is generally defined as an auditory perception in the absence of environmental sound stimulation. However, this definition is quite incomplete as it omits an essential aspect, the patient's point of view. This point of view constitutes, first and foremost, a global and unified lived experience, which is not only sensory (localization, loudness, pitch and tone), but also cognitive (thoughts, attentiveness, behaviors) and emotional (discomfort, suffering).

A robust enzyme-linked immunosorbent assay to measure serum ramucirumab concentrations.

Ramucirumab, an anti-VEGFR2 monoclonal antibody, has been approved for the treatment of metastatic gastric and colorectal cancer. An assay measuring ramucirumab serum concentrations was needed to investigate its pharmacokinetics and concentration-response relationship. An ELISA was developed and validated according to the international guidelines for ligand-binding assays.

First assessment of sophrology for the treatment of subjective tinnitus.

Objectives: To assess (without comparison versus controls) the efficacy of a sophrology protocol adapted to disabling subjective tinnitus, in diminishing the handicap induced by perception of tinnitus.

Materials And Methods: One hundred and forty consecutive patients, aged 18-83 years, underwent a protocol comprising 6-8 sessions of sophrology over a 2-4 month period. Impact was assessed on pre- to post-treatment progression on the Tinnitus Handicap Inventory (THI), a validated questionnaire measuring handicap induced by tinnitus.

Monoclonal Antibodies Targeting the IL-17/IL-17RA Axis: An Opportunity to Improve the Efficiency of Anti-VEGF Therapy in Fighting Metastatic Colorectal Cancer?

Colorectal cancer is a major problem for public health worldwide because of its frequency and its severity. Many efforts have been carried to target the vascular endothelial growth factor (VEGF) pathway, one of the main promoters of pathological angiogenesis. Therapeutic monoclonal antibodies against VEGF have emerged as essential biopharmaceuticals for the advanced stages of the disease, in association with appropriate backbone chemotherapy.

[Good practices with tinnitus in adult].

The interrogation is essential to trace the genesis of the tinnitus and to appreciate its repercussion. Clinical examination should look for a local, vascular or cervical cause. The ENT consultation with audiogram and tinnitus evaluation is essential to know the characteristics of the tinnitus and to consider the treatment.

Influence of FcγRIIIA genetic polymorphism on T-lymphocyte depletion induced by rabbit antithymocyte globulins in kidney transplant patients.

Introduction: Polyclonal antithymocyte globulins (ATG) have been used in transplantation for several decades, but the sources of the interindividual variability of their effect are poorly understood. An influence of the FCGR3A-158V/F genetic polymorphism on the horse ATG concentration-effect relationship was reported in kidney transplant patients. The objective of the present study was to confirm the influence of the FCGR3A polymorphism on the extent of lymphocyte depletion in kidney transplant patients treated with rabbit antithymocyte globulin (r-ATG).

Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies.

The neonatal Fc receptor (FcRn) encoded by FCGRT is known to be involved in the pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs). Variability in the expression of FCGRT gene and consequently in the FcRn protein level could explain differences in PK observed between patients treated with mAbs. We studied whether the previously described variable number tandem repeat (VNTR) or copy number variation (CNV) of FCGRT are associated with individual variations of PK parameters of cetuximab.

FCGR2C genotyping by pyrosequencing reveals linkage disequilibrium with FCGR3A V158F and FCGR2A H131R polymorphisms in a Caucasian population.

The FCGR3A-V158F and FCGR2A-H131R polymorphisms are associated with clinical responses to therapeutic mAbs and with immune thrombocytopenic purpura (ITP). The FCGR2C-ORF/STOP polymorphism, controlling FcγRIIC expression on natural killer cells and therefore FcγRIIC-mediated antibody dependent cell-mediated cytotoxicity, is also associated with ITP. Using a new pyrosequencing assay to determine this polymorphism in a control population, we observed the expected allele frequencies (ORF:12.

Association of Fcγ receptor IIIA variant with a subset of anti-topoisomerase I-positive patients in systemic sclerosis: a descriptive pilot study.

Hypothesizing a pathophysiological role of anti-topoisomerase I antibodies (anti-topo I) through autoantibody-dependent cell-mediated cytotoxicity (ADCC) and cytotoxic effectors expressing receptors for the Fc portion of IgG in systemic sclerosis (SSc), 267 SSc patients (56 with anti-topo I and 102 with anti-centromere antibodies (ACA)) were genotyped for the functional FCGR3A-V158F polymorphism. A descriptive analysis of patients according to their clinical and immunological status and FCGR3A-158 V/F genotypes was performed using multiple correspondence analysis. This descriptive analysis revealed an association between the FCGR3A-158 VV genotype and the presence of anti-topo I.

VEGF polymorphisms are associated with an increasing risk of developing renal cell carcinoma.

Purpose: Vascular endothelial cell growth factor is studied in different malignant tumors as a key endothelial cell mitogen. Many single nucleotide polymorphisms in the VEGF gene have been described. We compared VEGF gene polymorphisms between a control group and a renal cancer group.

[Implications of receptors for the Fc portion of IgG (FcgammaRs) in mechanism of action of therapeutic antibodies].

From several years ago, recombinant monoclonal antibodies have allowed a revolution in therapeutic approach of cancer patients. Whereas the clinical efficacy of many antibodies is now demonstrated, their mechanism of action in patients remains elusive. For antibodies targeting membrane antigens, they particularly resort to cytotoxic effectors, which expressed receptors for Fc portion of IgG (FcgammaRs).

[Neonatal Fc receptor, key control of immunoglobulins biodistribution].

In 1969, Brambell, while studying the long serum half-life of IgG and their ability to cross the materno-foetal barrier, attributed these two properties to the existence of a specific Fc receptor, which was later denominated FcRn for neonatal Fc receptor. The resolution of its structure revealed that it is a MHC class-I-like molecule. FcRn is able to load IgG and albumin in a pH-dependent manner.

IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab.

Objective: The chimeric anti-tumor necrosis factor-alpha antibody infliximab is known to induce antibodies-to-infliximab (ATI) in some treated patients. Immunogenicity in murine variable domains is expected; however, constant domains of its human heavy gamma1 chain may also be implicated as it expresses G1m1 and G1m17 allotypes. This allelic form may be immunogenic in patients that are homozygous for the G1m3 allotype commonly expressed in Caucasoid populations.

Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20.

Clinical studies have shown a large interindividual variability in rituximab exposure and its significant influence on clinical response in patients receiving similar doses of antibody. The aim of this study was to evaluate the influence of tumor burden on dose-concentration-response relationships of rituximab. Murine lymphoma cells (EL4, 8 x 10(3)), transduced with human CD20 cDNA and transfected with luciferase plasmid (EL4-huCD20-Luc), were intravenously injected into C57BL/6J mice.

Neutrophil role in in vivo anti-lymphoma activity of rituximab: FCGR3B-NA1/NA2 polymorphism does not influence response and survival after rituximab treatment.

Background: Neutrophils could play an important role in in vivo rituximab anti-lymphoma activity. FcgammaRIIIb is expressed only by neutrophils and FcgammaRIIIb-neutrophil antigen (NA)1/NA2 polymorphism influenced phagocytosis of immunoglobulin G1-opsonized particles. We formulated the hypothesis that if neutrophils are critical cells for in vivo rituximab activity, FcgammaRIIIb-NA1/NA2 polymorphism could influence the response to rituximab.

Fc gamma RIIIa expression is not increased on natural killer cells expressing the Fc gamma RIIIa-158V allotype.

The presence of a valine (V) versus a phenylanaline (F) at position 158 of Fc gamma RIIIa/CD16a improves the affinity for IgG and is associated with higher therapeutic response to rituximab. Increased CD16 expression on natural killer (NK) cells from donors with the VV or VF versus FF genotype has recently been reported. We indeed observed higher binding of the anti-CD16 monoclonal antibody (mAb) 3G8 on NK cells from V carriers (VV = VF > FF).

[Target antigens for therapeutic antibodies in oncology: many candidates, few successes].

Targeted therapies, especially monoclonal antibodies, have reached an increasing importance in oncology. High-throughput techniques have allowed the identification of numerous transcripts, proteins, or non-protein antigens, which have generated the concept of immunome. This epitope library constitutes a huge reservoir of candidate antigens susceptible to become some say the target of an antibody for passive immunotherapy.

Structure-function relationships of the variable domains of monoclonal antibodies approved for cancer treatment.

Due to their exquisite specificity for a given epitope on the target antigen, recombinant monoclonal antibodies (rmAb) can deliver "targeted therapy" in oncology. This review focuses on the structural bases of "antigen specificity" to aid clinical researchers and pharmacologists in managing these new drugs. The fine structure of the Fv (Fragment variable) module (combination of VH and VL domains) from the five unconjugated antibodies currently approved for cancer treatment, namely rituximab, cetuximab, alemtuzumab, trastuzumab and bevacizumab, is presented and analysed.

Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment.

Antibody humanisation through recombinant DNA technology was a key step in allowing monoclonal antibodies (mAbs) to reach the clinic, particularly for the treatment of cancer. As a consequence, they are less adapted to animal studies, although these studies continue to be important tools to study antibody distribution and action at the level of a whole organism. Moreover, preclinical studies in animals are mandatory before the approval of biologics license applications for mAbs by the U.

CXCL12 polymorphism and malignant cell dissemination/tissue infiltration in acute myeloid leukemia.

Stromal cell-derived factor 1 (SDF-1), a chemokine abundantly produced by the bone marrow microenvironment, and its receptor CXCR4 have crucial roles in malignant cell trafficking. In acute myeloid leukemia (AML), blasts invade the bloodstream and may localize in extramedullar sites, with variations from one patient to another. We hypothesized that a polymorphism in the SDF-1 coding gene (CXCL12 G801A) could influence blast dissemination and tissue infiltration in AML.

No association between C-reactive protein gene polymorphisms and decrease of C-reactive protein serum concentration after infliximab treatment in Crohn's disease.

We recently showed an association between the FCGR3A V/F polymorphism and the biological response [assessed on the basis of a C-reactive protein (CRP) concentration decrease] to infliximab in Crohn's disease. The CRP and FCGR3A genes are located on the same 1q23 locus. The present study aimed: (i) to exclude a linkage disequilibrium (LD) between the two genes and (ii) to study the association between CRP polymorphisms and the response to infliximab, particularly the decrease in CRP after treatment, in Crohn's disease patients.