Mostly studied in murine models, Ikaros--a factor that positively or negatively controls gene transcription--was first described as essential to lymphopoiesis until its involvement in numerous hematopoietic lineages was documented. Indeed, Ikaros is also active in murine erythropoiesis and more precisely during fetal to adult globin switching. Recently, these observations were confirmed by our team in a human context. We here review some of the most important characteristics of Ikaros, and detail more precisely how defects of Ikaros activity either by gene inactivation or mutation in mice, or by forced expression of dominant negative isoforms in human precursor cells, modify the erythroid differentiation. An increased cell death, together with decreased cell proliferation, decreased expression of erythroid-specific genes including GATA1, and a delay in fetal to adult globin switching were observed. At the same time, myeloid differentiation was slightly favoured thus suggesting that Ikaros could be involved in the control of the myeloid/erythroid commitment.

In mammals, embryonic and extraembryonic cell lineages segregate during the first steps of cell differentiation in the preimplantation embryo. Indeed, mammal embryos contain very low energy stocks and thus get ready for implantation very early to be able to absorb nutrients from the mother, first through the yolk sac and then through the placenta. These first steps involve classical genetic and morphogenetic processes as well as specific mechanisms of early embryo development such as epigenetic reprogramming and maintenance of pluripotent cells. Embryo analysis led to the isolation of embryonic stem (ES) cells, granted by the 2007 Nobel prize of Medicine (to M. Evans, M. Capecchi and O. Smithies) and which offer strong hopes for cell therapy.

The destruction of articular cartilage represents the outcome of most inflammatory and degenerative rheumatic diseases and leads to severe disability. Articular cartilage being unable to repair spontaneously, alterations of the joint surface often results in end-stage osteoarthritis, requiring surgical intervention and total joint replacement. This makes damaged tissues repair a major challenge in our aging society. Cartilage harbors only one cell type, the chondrocyte, which synthesizes and secretes specific matrix proteins such as type II collagen and high molecular weight proteoglycans. Matrix proteins are responsible for the conservation of the chondrocyte phenotype and the maintenance of the mechanical functions of cartilage. Development of therapeutic strategies for cartilage repair should thus comprise not only the replacement of lost cartilage cells but also that of extracellular matrix with cartilage-like properties. Different protocols are under investigation. The most commonly employed materials include transplantation of autologous osteochondral tissue. More recently, cell-based therapies using autologous mature chondrocytes or pre-chondrogenic stem cells have drawn particular attention. Tissue-engineering procedures represent the actual trend in cartilage repair. This approach combines biodegradable polymeric three-dimensional matrixes and isolated prechondrogenic stem cells. The cells are seeded within the biocompatible matrix and then implanted into the joint. Numerous non-degradable and degradable polymers, which efficiently "mimic" the natural surroundings of cartilage cells, are currently under investigation.

The definition of targets in the metastatic process has been a major step. Targeted therapy is composed of molecules which block these targets including ligand-binding antibody or receptor-inhibitors. Their mechanisms of action are not limited to angiogenesis but also concern apoptosis, bone marrow progenitor stem cells, vascularisation and immune response. An important number of drugs is still approved. However the metastatic disease is not yet curable. A better understanding will lead to develop others new targeted molecules or more efficient combination therapy.

The treatment of full thickness articular defects remains a challenging problem for the orthopaedic surgeon. Beside bone marrow stimulation techniques (microfractures) and autologous osteochondral mosaicplasty, a variety of procedures have been proposed to promote the healing of articular lesions by cultured competent cells. Tissue engineering is an emerging field, whose goal is to repair or replace tissues and organs by delivering the appropriate cells, biomaterials and signaling factors to diseased or damaged areas. In this article, we review the preclinical and clinical literature reported on the fabrication of implantable cartilage structures from chondrocytes and mesenchymal stem cells and discuss potential areas of development in the field of cartilage repair. Before routine use of engineered cartilage grafts in the clinic, the safety and efficacy of these therapies need to be validated in prospective human clinical trials.

Human and animal hepatocytes are now widely used for drug metabolism and interaction studies in the drug development process. However, their phenotypic instability and the absence of cell division in primary culture limit their interest for toxicity studies. Hepatoma cell lines are also used but they express very low levels, if any, of cytochromes P450 (CYP) that are essential for metabolism of a number of drugs and other chemicals. A new human hepatoma cell line, named HepaRG, possesses both the metabolic capacity of human hepatocytes in primary culture and the indefinite proliferation potential of hepatoma cell lines. After two weeks of confluence HepaRG cells express the main CYP, phase 2 enzymes, plasma membrane transporters as well as the nuclear receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR). They can be maintained functionally relatively stable for several days or even a few weeks before being seeded and proliferating again, making them suitable for chronic toxicity and mutagenesis/carcinogenesis studies. Another in vitro model system is represented by extrahepatic stem cells but experimental culture conditions allowing their differentiation into mature hepatocytes have not been defined yet.

The present guidelines on the management of extensive disease small cell lung cancer (SCLC) were formulated by the European Lung Cancer Working Party (ELCWP) in October 2007. They are designed to answer the following nine questions : 1) What is the definition of extensive disease? 2) What are the active drugs? 3) What is the best induction regimen? 4) Is there a role for maintenance chemotherapy? 5) Is there a role for dose-intensive chemotherapy? 6) Is there a role for the use of haematopoietic growth factors and stem cells support? 7) Is there a role for alternating or sequential chemotherapy? 8) Is there a role for biological treatments? 9) Is there a place for second-line chemotherapy ?

Microchimerism is defined as the persistence within an individual of a low level of cells or DNA derived from another individual. The most common source of microchimerism is pregnancy. Bidirectional transplacental materno-fetal cell trafficking occurs during most pregnancies and chimeric cells can persist in blood or tissues for decades after childbirth. It can leads to fetal (fetal-maternal transfer) or maternal (maternal-fetal transfer) microchimerism. Characterization of cells implied in microchimerism is incompletely known: it could be at least partly, fetal progenitors cells with ability of self renewal and specific differentiation according to the surrounding tissue. The transferred fetal cells can be recruited in various injured maternal tissues (auto-immune diseases, stroma of various tumours associated with pregnancy) but their precise biological role is uncertain. Microchimerism has been implicated in the pathogenesis of autoimmune diseases (especially systemic sclerosis) but current data suggest that fetal microchimeric cells may participate in maternal physiological response and injured tissue repair. Similar observations were made with maternal microchimerism (excepted with juvenile idiopathic inflammatory myopathies whose immunopathogenesis is probably related with transfer of maternal immune cells).

Ocular or thermal burns account for 7.7%-18% of ocular trauma. The majority of victims are young. The burns occur in the setting of accidents at work or in the home, or during a physical attack. Chemical burns by strong acids or bases are responsible for the most serious injuries. Associated with the destruction of limbal stem cells, they present as recurrent epithelial ulcerations, chronic stromal ulcers, deep stromal revascularization, conjunctival overlap, or even corneal perforation. The initial clinical exam is sometimes difficult to perform in the presence of burning symptoms. Nevertheless, it enables the physician to classify the injury, establish a prognosis, and most importantly, guide the therapeutic management. The Roper-Hall modification of the Hughes classification system is the most widely utilized, broken down into stages based on the size of the stromal opacity and the extent of possible limbal ischemia. This classification is now favorably supplemented by those proposed by Dua and Wagoner, which are based on the extent of the limbal stem cell deficiency. The prognosis of the more serious forms of ocular burns has markedly improved over the last decade because of a better understanding of the physiology of the corneal epithelium. Surgical techniques aimed at restoring the destroyed limbal stem cells have altered the prognosis of severe corneal burns. In order to decrease the incidence of burns, prevention, particularly in industry, is essential.

During mitosis each daughter cell inherits a full copy of the maternal genomic material. DNA replication, however, is an imprecise process, thus errors can arise resulting in potentially deleterious mutations over extended rounds of cell division and these may lead to cancinogenesis. Over thirty years ago, J. Cairns proposed that a cell could avoid the accumulation of mutations arising from DNA replication if all template DNA strands are inherited in one daughter cell during cell division, thus giving rise to the notion of << immortal >> DNA strands. In this model the stem cells would retain the template DNA (older) strands. Proving or disproving this notion experimentally has been challenging. Further, it has recently become apparent that epigenetic regulation of gene expression plays a critical role in governing cell states, self-renewal and differentiation. In light of these data, can the phenomenon on template DNA strand segregation also reflect this epigenetic signature? In this review we explore these notions, discuss the evidence in support of this theory, the implications, and some of the mechanisms which could explain this phenomenon.

Hypereosinophilia is a common clinical finding, and is generally associated with an underlying disease, mainly parasitosis, atopic disorders, drug hypersensitivity, and certain solid and haematological malignancies. Appropriate therapeutic management requires identification of the cause, through careful clinical examination and various technical investigations. Occasionally, thorough diagnostic work-up fails to identify an underlying disorder; the term hypereosinophilic syndrome is used when moderate or severe hypereosinophilia is associated with multi-organ involvement. Indeed, whatever its cause, when the blood eosinophil level is greater than 1500 per microfiter, there is a significant risk of complications directly related to the presence of eosinophils in tissues. The major target organs are the skin, lungs, digestive system, nervous system, and the heart. Reduction of blood eosinophil levels becomes an aim in itself in such cases, and recent studies on pathogenesis of hypereosinophilic syndrome have had an impact on the choice of therapeutic agents used to this end. Imatinib has become first line treatment for a disease variant associated with a somatic mutation involving pluripotent hematopoietic stem cells that generates autonomous tyrosine kinase activity, leading to clonal expansion of eosinophils. For all other patients, gluco-corticoids remain first choice. In case of cortico-resistance or if a cortico-sparing agent is required, options include interferon-alpha, hydroxyurea, or mepolizumab, a monoclonal anti-IL-5 antibody that has recently shown efficacy as a cortico-sparing agent for hypereosinophilic syndrome in a well-conducted clinical trial.

In the field of oncohematology, the rationale for the use of blood transfusion relies both on the proliferative advantage of the transformed clone over the others and on hematologic toxicity of chemotherapy. In France, transfusion thresholds are established by a consensus conference organized by the Agence française de sécurité sanitaire des produits de santé (Afssaps), the French health products safety agency: 80g/l for PRC and 10G/l for platelets concentrates in patients without additional hemorragic risk factors. For FFP especially in TTP, thresholds are more patient-related. Transfusion for sickle cell patients remains a scientific challenge.

Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration. Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions. Although MSC immunomodulating properties are not yet completely understood, their low immunogenic potential can be used as a therapeutic tool not only for regenerative medicine, but also for the treatment of graft-versus-host disease (GVHD) after bone marrow transplantation as well as for specific cases of severe refractory autoimmune diseases. Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction. Phase I-II studies are in progress in various countries to investigate the potential benefit from MSC due to their immunosuppressive properties, as an adjunctive therapy for severe refractory autoimmune disease.

Interventional cardiology has dramatically developed since its introduction in 1977. Angioplasty represents the first choice for coronary reperfusion during acute myocardial infarction with thromboaspiration and stenting of the culprit lesion. In acute coronary syndroms and stable angina or silent ischemia despite optimal medical treatment, angioplasty is today an excellent option for coronary revascularization which includes a technologic offer adapted to various clinical and anatomical situations (specific guidewires, rotative atherectomy, distal protection devices and drug eluting stents that reduce the risk of coronary reintervention after initial angioplasty). For patient with severe ischemic left ventricular dysfunction, interventional rythmology can improve patient prognosis by a limitation of lethal ventricular fibrillation. Despite the hope that intracoronary cell transplantation could save myocardial cells, several randomized control trials have given various and disappointing results concerning the potential improvement of left ventricular function. Interventional cardiology nowadays offers global technical solutions for more and more patients suffering from ischemic cardiomyopathy.

The first transgenic experiments were described in the seventies and this technology expended in the eighties with the development of the microinjection, of embryonic stem cells and more recently of the animal cloning procedure. So far, it was only poorly influenced by the progress in gene therapy. The emergence of non-replicating lentiviral vectors and their use in transgenic experiments in the last ten years have validated a new technology that could be applied to various animal species. The aim of this review is to compare the different existing approaches and to try to highlight how, despite some limitations, these new vectors increase the range of applications of transgenesis in some species and open some new ones.