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International audience; In the last few decades, the epithelial cell adhesion molecule (EpCAM) has received increased attention as the main membrane marker used in many enrichment technologies to isolate circulating tumor cells (CTCs). Although there has been a great deal of progress in the implementation of EpCAM-based CTC detection technologies in medical settings, several issues continue to limit their clinical utility. The biology of EpCAM and its role are not completely understood but evidence suggests that the expression of this epithelial cell-surface protein is crucial for metastasis-competent CTCs and may not be lost completely during the epithelial-to-mesenchymal transition. In this review, we summarize the most significant advantages and disadvantages of using EpCAM as a marker for CTC enrichment and its potential biological role in the metastatic cascade.

International audience; Epigenetic regulation is altered in many diseases, in particular in cancer. Several molecules acting on the epigenetic regulation are in clinical trials, some of which are already approved for the treatment of haematological cancers. We will summarize here the latest advances in the discovery of chemical molecules acting on DNA and histone methylation. These new molecules bring new promises but also limitations that we will discuss.; La régulation épigénétique est altérée dans de nombreuses maladies, dont le cancer. Plusieurs molécules agissant sur la régulation épigénétique sont testées en phase clinique ou déjà approuvées pour le traitement de leucémies, par exemple. Nous allons ici résumer les dernières avancées concernant la découverte de molécules chimiques agissant sur la méthylation de l'ADN et des histones. Ces molécules apportent de nouvelles promesses mais ont aussi des limites que nous allons discuter.

International audience; Introduction:Mitogen-activated protein kinase (MAPK) pathway is known to be involved in the tumorigenesis of cancer cells including non-small cell lung cancer (NSCLC) and kinases involved in this pathway are frequently mutated. The development of new targeted therapies in cancer has led to the evaluation of MEK-inhibitors. Areas covered: This article reviews different studies using trametinib alone, in combination with other targeted therapies or associated with other non-targeted therapies in NSCLC, with a focus on KRAS mutant and BRAF mutant NSCLC. Expert commentary: Trametinib demonstrated activity in association with a BRAF inhibitor when BRAF was mutated. The combination of trametinib and dabrafenib has been approved for this population of BRAF mutant NSCLC patients. For KRAS mutant NSCLC, the combination of trametinib with chemotherapy has showed promising results and should be further assessed. Several clinical trials are ongoing, assessing trametinib in combination with other targeted therapies. In addition, preclinical studies suggest a synergistic effect of trametinib in combination with immune checkpoint inhibitors and such combinations should be studied in clinical trials.

International audience; Inhibitors of the receptor tyrosine kinase (RTK) MET have been ineffective at treating cancer, possibly because of lack of knowledge that would allow selection of tumors likely to respond to this treatment. In contrast, specific epidermal growth factor receptor (EGFR) inhibitors have been used successfully against lung tumors displaying activating mutations in the kinase domain of EGFR. Recent publications describe a set of mutations causing MET exon 14 skipping, and importantly, several case reports describe objective responses to MET-targeting tyrosine kinase inhibitors in patients with such mutations. These observations suggest a novel therapeutic strategy for fighting cancer, especially in the lung. Exon 14 encodes the MET juxtamembrane domain targeted by mechanisms that negatively regulate receptor stability and activity. In this review, we describe the molecular mechanisms leading first to exon 14 skipping and then to activation of the MET receptor and how this process differs from that triggered by classical RTK-activating mutations in the kinase domain. We detail the clinical characteristics of patients carrying these mutations and the sensitivity of their tumors to MET inhibitors. Lastly, we discuss future challenges related to MET mutations in cancers, including patient screening and anticipating resistance to MET inhibitors.

International audience; Pancreatic adenocarcinoma remains a devastating disease with a 5-year survival rate not exceeding 6%. Treatment of this disease remains a major challenge. This article reviews the state-of-the-art in the management of this disease and the new innovative approaches that may help to accelerate progress in treating its victims. After careful pre-therapeutic evaluation, only 15-20% of patients diagnosed with a pancreatic cancer (PC) are eligible for upfront radical surgery. After R0 or R1 resection in such patients, evidence suggests a significantly positive impact on survival of adjuvant chemotherapy comprising 6 months of gemcitabine or fluorouracil/folinic acid. Delayed adjuvant chemoradiation is considered as an option in cases of positive margins. Borderline resectable pancreatic cancer (BRPC) is defined as a tumour involving the mesenteric vasculature to a limited extend. Resection of these tumours is technically feasible, yet runs the high risk of a R1 resection. Neoadjuvant treatment probably offers the best chance of achieving successful R0 resection and long-term survival, but the best treatment options should be determined in prospective randomised studies. Gemcitabine has for 15 years been the only validated therapy for advanced PC. Following decades of negative phase III studies, increasing evidence now suggests that further significant improvements to overall survival can be achieved via either Folfirinox or gemcitabine + nab-paclitaxel regimens. Progress in systemic therapy may improve the chances of resection in borderline resectable pancreatic cancer (BRPC) or locally advanced PC. This requires first enhancing knowledge of the genetic events driving carcinogenesis, which may then be translated into clinical studies.

International audience; Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

International audience; Mortality from cardiovascular diseases (CVD) represents the primary cause of death worldwide. Prevention or treatment of atherosclerosis and its clinical sequelae is a central goal in the management of patients with established vascular disease or those at high-risk for vascular events. This paper provides a review of the contemporary pharmacological armamentarium targeting atherosclerosis and also highlights strategies to support future clinical trial design. Powering future trials targeting LDL-cholesterol to its absolute reduction and including patients with a higher LDL-C despite optimal medical therapy (or unable to tolerate statins) will increase the odds of meaningful results. Mendelian randomization studies may identify new causal risk factors for CVD that would help in the selection of the patients most likely to benefit from a specific new compound. Furthermore, imaging techniques integrating a morphological and functional assessment such as IVUS, OCT, PET/CT and PET/MRI may represent in a near future robust "soft" endpoints to support successful translation of early research into meaningful phase III clinical outcome trials.

International audience; Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.

International audience; Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer

International audience; In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies.; En 1984, le récepteur à activité tyrosine kinase Met et son ligand l’HGF (hepatocyte growth factor)/SF (scatter factor) sont découverts grâce à leur aptitude à induire la transformation et la prolifération cellulaires. Trois décennies ont permis de mettre en évidence leur rôle fondamental dans le déve­loppement et l’homéostasie de nombreuses structures, notamment des organes épithéliaux. Cette même période a permis de décrypter les bases structurales de leur interaction, ainsi qu’un réseau de signalisation complexe. Parallèlement, l’implication de la dérégulation de Met dans la tumorigenèse, supposée dès sa découverte, a été démontrée ; elle est associée à un mauvais pronostic dans de nombreux cancers. Le rôle de cette dérégulation dans des phénomènes de résistance aux thérapies actuelles commence également à être déchiffré. Sur la base de ces données, des compagnies pharmaceutiques ont développé une grande diversité d’inhibiteurs ciblant l’HGF/SF ou le récepteur Met, dont certains sont actuellement évalués dans des essais cliniques de phase III. Nous proposons dans cette revue de retracer le parcours exemplaire des recherches sur le récepteur Met, qui auront permis en trente ans de passer de la découverte fondamentale d’un oncogène au développement de thérapies ciblant son action. Cependant, de nombreuses questions restent en suspens. Par exemple, l’implication de Met dans plusieurs étapes du développement reste à préciser, de même que les mécanismes faisant de ce récepteur un facteur de résistance aux traitements actuels ou le développement probable de résistances aux thérapies ciblant sa propre activité.

International audience; PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.

International audience; The Smoothened (Smo) receptor is a key transducer of the Hedgehog (Hh) signaling pathway, which plays a critical role in tissue maintenance and repair. Recent studies have highlighted the therapeutic value of Smo antagonists for treating Hh-linked cancers. Research on Smo agonists indicates that these molecules are important not only for delineating canonical versus noncanonical Hh signaling but also for understanding the role of Smo in physiological and pathological conditions. This review provides an update on the potential therapeutic importance of Smo modulators, and unravels the increasing complexity of its pharmacology with regard to clinical implications.

International audience; Rationale:The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.; Objective:The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms.; Method:Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions.; Results:The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity.; Conclusions:ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.

In 1984, the Met receptor and its ligand, the HGF/SF, were discovered thanks to their ability to induce cell transformation and proliferation. Thirty years of research highlighted their crucial role in the development and homeostasis of various structures, including many epithelial organs. This period also allowed unraveling the structural basis of their interaction and their complex signaling network. In parallel, Met was shown to be deregulated and associated with a poor prognosis in many cancers. Met involvement in resistance to current therapies is also being deciphered. Based on these data, pharmaceutical companies developed a variety of Met inhibitors, some of which are evaluated in phase III clinical trials. In this review, we trace the exemplary track record of research on Met receptor, which allowed moving from bench to bedside through the development of therapies targeting its activity. Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Met-targeted therapies., En 1984, le récepteur à activité tyrosine kinase Met et son ligand l’HGF (hepatocyte growth factor)/SF (scatter factor) sont découverts grâce à leur aptitude à induire la transformation et la prolifération cellulaires. Trois décennies ont permis de mettre en évidence leur rôle fondamental dans le déve­loppement et l’homéostasie de nombreuses structures, notamment des organes épithéliaux. Cette même période a permis de décrypter les bases structurales de leur interaction, ainsi qu’un réseau de signalisation complexe. Parallèlement, l’implication de la dérégulation de Met dans la tumorigenèse, supposée dès sa découverte, a été démontrée ; elle est associée à un mauvais pronostic dans de nombreux cancers. Le rôle de cette dérégulation dans des phénomènes de résistance aux thérapies actuelles commence également à être déchiffré. Sur la base de ces données, des compagnies pharmaceutiques ont développé une grande diversité d’inhibiteurs ciblant l’HGF/SF ou le récepteur Met, dont certains sont actuellement évalués dans des essais cliniques de phase III. Nous proposons dans cette revue de retracer le parcours exemplaire des recherches sur le récepteur Met, qui auront permis en trente ans de passer de la découverte fondamentale d’un oncogène au développement de thérapies ciblant son action. Cependant, de nombreuses questions restent en suspens. Par exemple, l’implication de Met dans plusieurs étapes du développement reste à préciser, de même que les mécanismes faisant de ce récepteur un facteur de résistance aux traitements actuels ou le développement probable de résistances aux thérapies ciblant sa propre activité.

International audience; Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.

International audience; The spectrum of chemotherapy's cardiac side effect of chemotherapy has expanded with the new combinations of cytotoxic and targeted therapies over the past 10 years. Moreover, cancer therapy administrated to "new" populations, especially elderly patients or patients with cardiovascular disease and/or coronary artery disease history, has increased considerably. According to the American College of Cardiology and American Heart Association (ACC/AHA), patients receiving chemotherapy can be considered in the A group of heart failure. Many cardiovascular adverse effects appear with cancer therapy and suspend treatment purchase, or leading to an alteration of quality of life, and increasing mortality risks. The most clinically evident cardiotoxicity and best known is the anthracyclines adverse effect. Other cytotoxic are associated with a significant risk of cardiovascular complications include alkylating agents such as 5-fluorouracil and paclitaxel. Cardiovascular adverse effects are associated with the use of targeted therapies such as tyrosine kinase inhibitors: trastuzumab, bevacizumab. At the same time, drugs used to hematological malignancies, as acid all-trans-retinoic acid and arsenic trioxide are cardiotoxics. The most serious cardiac complications of cancer therapies is heart congestive failure, mainly due to the use of anthracyclines, cyclophosphamide and trastuzumab, usually at high doses. Myocardial ischemia is mainly caused by interferon and antimetabolites. Other side effects may occur such as hypotension, hypertension, arrhythmias and conduction disturbances, pericarditis, and thromboembolic complications.

International audience; Parkinson's disease is characterized by a triad of cardinal motor symptoms (bradykinesia, rigidity and tremor) resulting from the loss of dopaminergic neurons in the substantia nigra. This synucleinopathy is classified in the larger group of Lewy body disorders. Currently, these symptoms are relatively well alleviated by drugs that restore dopaminergic neurotransmission, andlor by deep brain stimulation. It is not yet possible to halt the underlying degeneration, or to treat symptoms due to non-dopaminergic neuron damage. This review examines the mechanisms of neuronal degeneration in Parkinson's disease, new targets for neuroprotection, and the mechanisms causing symptoms resistant to current treatments.

International audience; The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αβ) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.

International audience; The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αβ) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.

The purpose of this special edition of Hormones & Cancer is to relay the exciting new developments in the adrenal cancer field that have emerged in the last few years. The very successful 3rd International Adrenal Cancer Symposium: From Molecular Pathogenesis to Clinical Outcome held in Wurzburg, Germany earlier this year served as a backdrop for this project. This meeting followed two highly stimulating International Adrenal Cancer Symposia organized in Ann Arbor (Michigan, USA) and continued to be a key event in the field of adrenal cancer. More than 140 clinicians and investigators from 17 different countries attended the meeting with more than 30 talks covering the whole spectrum of this rare disease. However, rather than compile manuscripts as simple summaries of the symposium to serve as a “proceeding”, we elected to solicit bona fide state of the art “expert reviews” of various aspects of scientific and clinical import in the field of adrenal cancer. All articles were peer reviewed by experts in the endocrine, oncology, and specialized adrenal cancer field. Serendipitously, we were simultaneously given the opportunity to serve as guest editors for two separate “special editions” in both the Endocrine Society/Springer journal Hormones & Cancer and the Elsevier journal Molecular and Cellular Endocrinology. We elected to publish the more clinically relevant articles in Hormones & Cancer and the more basic articles in Molecular and Cellular Endocrinology. Readers should consider these two publications’ companion editions that detail the state of the science and clinical care pertinent to this disease. In Hormones & Cancer, articles are focused on the topics of “Advances in the diagnostic and prognostic markers of adrenocortical carcinoma” (including contributions by Auchus, Papotti et al., Young, Hahner and Sundin, and Deandreis et al.) and “Current and emerging therapies for adrenocortical carcinoma” (with contributions by Baudin et al., Porpiglia et al., Berruti et al., and Demeure et al.). In the companion Molecular and Cellular Endocrinology —Adrenal Cancer: Scientific Advances Special Edition, articles provide a comprehensive view from “Adrenal development—implications for tumorigenesis” (contributions from Simon and Hammer, Gardiner et al., Lauter et al., and de Joussineau et al.) to the “Epidemiology of adrenocortical carcinoma” (contributions by Ribeiro et al., Figueiredo et al., and Almeida and Faria), “Cellular and animal models for adrenocortical carcinoma” (contributions by Wang and Rainey, Else, Luconi and Mannelli, and Wilson and Beuschlein) and “Genetics and genomics of adrenocortical carcinoma” (contributions by Berthon et al., Ribeiro and Latronico, Wasserman et al., Assie et al., and Singh et al.). The editors would like to thank Lisa K. Byrd for her administrative efforts through this process. Together with the companion Adrenal Cancer Special Edition published in Molecular and Cellular Endocrinology, she kept 102 authors informed and on task, handling a total of 25 manuscripts. Without her involvement, this special edition would not have been possible. We hope you will enjoy reading those papers as much as we did while preparing the journal issues.

International audience

International audience; Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.

International audience; INTRODUCTION: The presence of fibrosis is associated with alterations in organ architecture and is responsible for the morbidity of diseases including pneumopathies, systemic sclerosis, liver cirrhosis, chronic cardiovascular diseases, progressive kidney diseases and diabetes. Although a growing number of pro-fibrotic molecules, mediators and other pathways have been reported, there are currently very few antifibrotic molecules being evaluated in clinical trials. AREAS COVERED: Current knowledge about the contribution of lysophosphatidic acid (LPA), a bioactive mediator acting via specific G-protein coupled receptors (LPAR), in the etiology of fibrosis. In a number of organs, fibrosis is associated with increased LPA production as well as with increased expression of some LPAR subtypes (mainly LPA1R). LPAR(-/-) knockout mice and treatment of animal models with specific antagonists clearly demonstrate the contribution of LPA1R subtype to the development of kidney, lung, vascular and dermal fibrosis. The involvement of LPA in liver fibrosis is also strongly suspected but still unproven. EXPERT OPINION: Experiments in animal models clearly demonstrate that LPA1R antagonists have interesting anti-fibrotic potencies. This reveals promising perspectives for the design of new therapeutic approaches to prevent fibrosis-associated diseases. Nevertheless, the number of efficient LPA1R antagonists currently available is still low, and none of them has been used in clinical trials so far.

Selectins belong to the family of adhesion molecules that recognize sugars as ligands through their Carbohydrate Recognition Domain (CRD). There are three types of selectin: the L-selectin (CD62L), which is constitutively expressed by most leukocyte populations, the P-selectin (CD62P) is found on activated platelets and endothelial cells, and the E-selectin (CD62E) expressed by activated endothelial cells. These three molecules exhibit high homology in their structures. Selectin-ligand interactions are among the most studied protein-glycan interactions in biology. The selectins and theirs ligands are involved in regulating inflammatory and immunological events that occur at the interface of the bloodstream and vessel walls. Their molecular partners are surface glycoconjugates harboring groups of the sialyl-Lewis antigens. This review presents an inventory of our current knowledge on the structures and functions of selectins and their ligands. We also provide an update on their involvement in pathophysiological processes, especially during inflammation and tumor development., Les sélectines font partie de la famille des molécules d’adhérence et ont la particularité de posséder un domaine de liaison aux sucres, le CRD (Carbohydrate Recognition Domain). On distingue trois types de sélectine: la L-sélectine (CD62L) qui est exprimée constitutivement par la plupart des populations leucocytaires, la P-sélectine (CD62P) qui est retrouvée sur le s plaquettes et les cellules endothéliales et la E-sélectine (CD62E) exprimée par les cellules endothéliales activées. Ces trois molécules possèdent une forte homologie au niveau de leur séquence primaire et de leurs structures. Les interactions sélectine-ligand sont les plus étudiées parmi les interactions protéine-glycanne connues en biologie. Elles sont impliquées dans la régulation des évènements inflammatoires et immunologiques à l’interface paroi vasculaire/ circulation sanguine. Leurs partenaires moléculaires sont des glyco conjugués de surface exprimant des groupements de la famille des sialyl-Lewis. Cette revue présente l’état des lieux des connaissances sur la structure et l’expression des sélectines et de leurs ligands. Elle fait aussi le point sur leur implication en physiopathologie, principalement lors de l’inflammation et du développement tumoral